Introduction

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome to “What I Tell My Patients,” as this morning we talk about the management of head and neck cancer, and this actually is the first time in our 16 years at ONS that we’ve had this topic. We’re really excited about this today. We have a great faculty today. In a second I’m going to let them introduce themselves and also let them talk a little bit about what they do in their particular position. I think you’ll find that head and neck cancer is kind of like a different world and very, very interesting.

As we’re doing in all of our meetings this week we will be talking about unapproved uses of drugs. Consult the package insert for more specific information. The clinicians here in the room, all of the slides are on your iPad. If you have any questions you can also use the iPad to do that, and the same functions in the chat room to all the people on Zoom. If you’re all like still lying in bed probably not wanting to come over here, but that’s great because either way it’s going to be a great experience.

We have a 1-minute pre- and postmeeting survey in the chat room and on your iPad. If you take that you’ll get a lot more out of this experience today.

We are recording this, though, so in a couple weeks we’ll send you an email. For your colleagues who aren’t here this morning you can tell them how great the program was, and they should check it out, as well as all 10 of the programs that we’re doing here at ONS. This is our 5^th of 10 programs.

We really view this as kind of an integrated experience, not just talking about these specific cancers but also oncology nursing in general. We’d really like to make rounds here today. We’re not here to throw a bunch of slides up and just talk about data. To try to even enhance that more we actually did interviews with 8 nurses that we worked with in previous ONS meetings, and we weren’t able to work them in this year, and just chatted with them about taking care of patients.

We actually posted all 8 of these interviews. We created 85 videos that were all less than 90 seconds, we’re going to be putting them out on social media, if you want to get a preview of all of this. We’re just going to show a couple of these today, but we have an hour and a half of content like this. Researchtopractice.com/ONS2024Clips. If you want to check it out. Also maybe we’d love some suggestions on what to do with this fantastic content that we were able to obtain.

So with that, I wanted the faculty to introduce themselves and maybe just chat a little bit more because, again, this is kind of a new area for us, about what you do and also what you like about being in head and neck cancer. So I guess we can start out with Bob Ferris. You’re actually a surgeon. Can you talk about what you do and where you are?

DR FERRIS: Sure. Thanks very much, Neil. I really appreciate organizing this session. I’m a head and neck surgeon, and usually the surgeon is the first to identify the tumor, meet the patient, either from an ENT clinic, we are ear, nose and throat doctors with specialty training, in many tertiary centers, specialty training in head and neck surgery and multidisciplinary care. And sometimes patients are referred by a dentist when a lesion is seen, and so we get that first touch with the patient and often have to have that discussion about that they have a cancer and then begin to introduce the treatment team and all of the options.

DR LOVE: And I’m just kind of curious. What do you like about being in the field?

DR FERRIS: Well, the head and neck has all of the really key cranial nerves; speaking, breathing, swallowing, all of the senses for which we enjoy the world; eating, communicating and being able to go out and interact with other people. And so the thought that we could treat patients who have had their lives really turned upside down adding to that some of the salivary gland cancers where the facial nerve is involved, and there’s some disfigurement. So it is laden with a tremendous psychosocial aspect. And then coincidentally head and neck cancer during my training in the 90s was much more tobacco and alcohol exposures, carcinogens, and it’s now added the layer of human papillomavirus, so it’s just been a really evolving cancer to take care of with challenges that impact on patients’ quality of life.

DR LOVE: So Robert, you’re a medical oncologist. You two are 2 out of the 3 parts of the triad. We don’t have a radiation oncologist here, but that is the interdisciplinary triad.

DR FERRIS: We can usually speak for them.

DR HADDAD: We blame everything on radiation.

DR LOVE: So Robert, you’re at Dana-Farber. What kind of setup do you have there?

DR HADDAD: Yes. Good morning. Great to be here and thank you for inviting us. I work at the Dana-Farber in Boston. I’ve been there for 25 years, and I work in the multidisciplinary clinic. And obviously when patients are referred to me they already have a cancer diagnosis that’s made by Bob or a head and neck surgeon, and our role as we take on — medical oncology works as the quarterback for the patient, coordinating their care through those 7 weeks of chemoradiation, and then for the rest of their lives after that.

So a lot of what we’re going to talk about today is getting through those acute phases of the treatment, of radiation/chemotherapy, pre- or postsurgery and what happens afterward and how do we coordinate care for these patients and what happens on the short end and long term.

I work in the multidisciplinary clinic. So we have set up our clinics to be multi-D 5 days a week, so we work in the same physical space with surgical oncology, radiation oncology, nutrition, speech and language pathology, oral medicine, so we’re all in the same physical space talking to patients and managing their symptoms. And we’ll talk about this a lot today.

DR LOVE: So Meetal, you’re in Los Angeles, UCLA. What’s your setting?

MS DHARIA: So I’m a nurse practitioner, and I mainly deal with head and neck patients. I have an independent clinic, and I coach patients through their treatment, usually radiation concurrent with chemotherapy, and I help them manage a lot of the toxicities and basically make lots of referrals to help patients, support them through their treatment. I also am very involved with our clinical trials for our head and neck patients as well.

DR LOVE: And what is it about head and neck that you like?

MS DHARIA: I didn’t think going into head and neck that I’d actually enjoy it, but one of the things that’s really wonderful about being a nurse practitioner is that you can come alongside the patient and really help them with a lot of the toxicities. Chemotherapy with radiation is a highly toxic treatment, lots of side effects, so there’s a lot that I can do to help these patients to make this journey just a little bit easier.

DR LOVE: I didn’t ask you, Robert. What do you like about being in head and neck?

DR HADDAD: The most gratifying part really for me has been the multidisciplinary integration in this disease in particular which I think compared to all solid tumors it is really the solid tumor where you do actually need a small village to take care of 1 patient. And those people, if they’re not coming together for that patient, outcomes will be poor. And it’s clear from everything we know about head and neck cancer patients do better in high-volume academic, multidisciplinary integrated settings, and that is really important to think about setting up those clinics as much as you can. You might be working in a remote setting where you do not have access but think about how can you have access to those specialties even remotely because they are really important. Early intervention for speech and swallow, really essential, and I love managing these cancer patients because it gives me these constant interactions with large team members, and it’s very gratifying.

DR LOVE: That’s a great concept, though, of actually trying to reduplicate what you actually have physically but out there in the real world where you have to make it happen. Lynsey, how about there at Yale?

MS TEULINGS: Yeah. Hi, everyone. Happy to be here this morning. My name is Lynsey. I’m a nurse practitioner at the Smilow Cancer Hospital at Yale New Haven Health. I work exclusively in head and neck. I’ve been doing this for about 10 years. And my practice is independent but very collaborative with the 3 head and neck medical oncologists that I work with.

My role. I kind of get involved after the first patient visit. I like to tell my patients that the medical oncologist prescribes the treatment plan, and it’s part of my job to see it through. So I help with symptom management. I help with care coordination. Anything the patient needs to kind of get them through the prescribed course of treatment. And then I also do a lot of education and teaching in the follow-up realm as well.

DR LOVE: I’m sorry.

MS TEULINGS: I was just going to add that what I love about head and neck is that I think it’s a challenge. I said I’ve been doing this for a little while, but it’s important to note that even though head and neck cancer has a very high cure rate it’s I think one of the worst treatments you could possibly put somebody through. So we drag patients through the mud, but it’s great to see them when you finally get them to the other side. So…

DR LOVE: Yeah. I want to hear some of these cases and stories about how that actually plays out in practice. Very interesting. And also just before we kind of go through all the stuff so to speak we’re going to talk about the treatment both for localized and advanced disease.

Another really unusual and interesting aspect of this set of cancers, Bob, is the etiology and biologically how they end up in your clinic, the path that they get there. Can you kind of explain the 2 basic paths and really the difference in the biology and the whole vision of this disease.

DR FERRIS: Sure. I started to get a little bit into it, but traditionally head and neck cancer was caused by a lot of tobacco exposure, less so although we don’t want our patients to chew, it’s much more inhaled tobacco that we see, usually decades, that contributes to the cancer development but creates comorbidities that often come into play when we treat patients aggressively.

And then around — in the 90s over the course of that period of time, and then over the past 20 years a recognition that human papillomavirus, which is the primary cause of cervical cancer in women, was causing an increasing percentage of head and neck cancers. It’s particularly restricted to a subsite of the head and neck, the tonsil and the base of the tongue. There’s a circular ring of lymphoid tissue, tonsil tissue that the HPV seems to cause cancers. It doesn’t seem to cause cancers of the mouth, the front part of the tongue, or the voice box, but really that middle part of the tonsil.

And so as this has emerged it’s really separated our patients into 2 groups, and in many cases the HPV-positive ones have low or no smoking history. They tend to be folks that we might socialize with on a regular basis and pop up with a lump in the neck as opposed to the smoking-related folks who I think were the more traditional ones that come in with a long smoking/drinking history.

DR LOVE: So I’m curious also, Meetal, it’s 2 very different pathways biologically there. What’s it like to take care of a patient who has HPV related and maybe contrast it. We’re going to see this as we hear about your patients, but just globally when you know you’re going to go see a patient what are you thinking in each kind of scenario what you might be encountering, Meetal? Sorry. Lynsey?

MS TEULINGS: Oh.

DR LOVE: Sorry.

MS TEULINGS: So the actual treatment prescribed for HPV versus tobacco-associated cancers is not currently different, so we treat these patients very much the same. But obviously if you’re seeing somebody with a tobacco-related cancer a big part of outcome is making sure that they stop smoking, so I think that’s one major difference between how we treat the 2 types.

DR LOVE: So we had mentioned that we met with 8 of the nurses that we’ve worked with over the years and sounded them out about a number of issues. And this is Tiffany Richards. She’s actually from MD Anderson. She focuses on myeloma, but when I was chatting with her she brought up the issue of assessing the support system of the family, and I’ll be curious what your thoughts are about her thoughts. Here’s Tiffany.

DR RICHARDS: I always start off when I’m talking to a patient to make sure that I address also caregiver concerns and making sure that the caregivers know that they also can contact us if a patient is experiencing a side effect, particularly when it comes to something like irritability from steroids. And I think by doing that you develop a connection with the caregiver so that the caregiver knows that you care about them, as well, not just the patient, because they’re part of that dynamic.

I also think if a patient comes by themselves asking what kind of support that they have at home and to see if they have somebody that can come with them to appointments. And some patients may not want to, but then that’s a decision that they’re entitled to make, but also making sure the patients realize the side effects that they may have while they’re undergoing their infusion. And just particularly that first infusion when they’re coming in after they’re diagnosed, that’s stressful, it’s anxiety producing, and letting patients know that it might just be a good idea to have a support system, somebody that’s a support system at that first meeting because it’s scary.

I think it’s important that they know that it’s okay for them to have that support.

DR LOVE: So Meetal, any thoughts about this? And how do you assess the family of your patients and surroundings?

MS DHARIA: Yeah. So usually when I meet a patient, and I usually actually go in for the consult, I usually walk in the room, and I say to the patient, if they’ve got someone sitting there, who did you bring with you today. And I listen very carefully as to how they’re introducing the other person that’s in the room. Are they saying, oh, it’s a neighbor who just drove me here or are they telling me that this is their second pair of ears? So the degree of relationship is extremely important.

And if I do find that they are a significant other, and they are going to be part of the patient’s treatment team, and that’s how I see them, I involve them with every step of the care. And I will say to them these are the side effects, please help the patient report them if they happen between visits. But we become very reliant on family and significant others during treatment.

The Biology of Head and Neck Cancer

DR LOVE: So let’s talk a little bit more about the management of these patients, and Bob, maybe you can talk a little bit about the anatomy of where you see these cancers and how that affects the way you’re going to approach these patients initially.

DR FERRIS: Sure. Just to go a little bit in more detail, we think about the head and neck in 3 different subsites. The front part of the mouth, we usually say the part that you can see if they open it, where they stick their tongue out. That tends to be — and that has been a pretty stable subset, about 30% or 40% of the disease, very tobacco/alcohol associated. The important things are the tongue, the jawbone, things that are very important that if affected are going to have to be incorporated into treatment. You can see right there the oral cavity on the left.

Now going into, there in the yellow, the oropharynx. The oropharynx has basically 3 components; the tonsil, the base of the tongue and then you’d say the soft palate or uvula. And the tonsil and base of the tongue have the lymphoepithelium. There’s immune cells, and that may have some reason why a virus, human papillomavirus, causes it.

A little above the yellow, in the green, is the nasopharynx. There’s another virus that causes head and neck cancer called nasopharyngeal carcinoma, and that we don’t see much in Western countries. That is over in Southeast Asia. And Epstein-Barr virus causes nasopharyngeal carcinoma in that green area, the nasopharynx. But all of it is lymphoid tissue.

And then further down the larynx and hypopharynx, in the blue, which is where voice formation, where swallowing occurs and the airway.

And so there are different considerations. The front part of the mouth you’ve got speaking and swallowing and being able to articulate and then with the jawbone having disfigurement if portions of the jawbone have cancer invasion. The tonsil and the base of the tongue are really important for swallowing. That’s one of the key things we figure out when we’re treating a patient is how well they’re swallowing if portions of the base of the tongue, which is so important for swallowing, are involved.

And then further back that third section in blue is airway, the swallowing and speaking. That’s where the vocal cords are, as you see right by there, by the larynx.

The Multidisciplinary Treatment of Head and Neck Cancer

DR LOVE: So Robert, can you talk about as a medical oncologist globally what you’re thinking about as a global strategy, chemoradiation or other approaches, based on where it is and how big it is, what the stage is, how you think through a global treatment plan that your team is going to implement, Robert.

DR HADDAD: Yeah. So there are 3 main modalities for treatment that we use when approaching head and neck cancer. So those are surgery, radiation and chemotherapy, and many patients will require 1, 2 or 3 of these modalities. And this is one really situation where there are often cases and patients where there are more than 2 or 3 options available to the patient.

The biggest conversation that happens on that first visit really is going to be is this surgically resectable disease yes or no. So as Bob mentioned, one simple way to think about the initial approach of head and neck cancer is when you’re dealing with the oral cavity, so everything that’s oral tongue, everything that’s anterior, the usual course is you operate first, so oral cavity you operate first. When you’re dealing with the posterior location tumors, when you get to the larynx and hypopharynx, the usual course is not to operate first, is to think about organ preservation with radiation or radiation and chemotherapy. So anterior you operate, that’s the oral cavity, posterior you don’t usually operate, it’s radiation/chemo.

Where there will be tons of overlap, and the longest conversation we have now, are in the oropharynx, which is where HPV head and neck cancer occurs, because in the oropharynx for most patients you have both a surgical and a nonsurgical approach available to the patient. And the side effects of these 2 interventions are quite different, and the implications of having surgery versus no surgery/radiation can be quite significant. And those conversations then become really to the point where the patient has to be part of this conversation about their personal preference and what they perceive as important to them and understanding the implications of surgery followed by radiation or up-front radiation/chemotherapy.

So a simple way to think about this for me as a medical oncologist; oral cavity I want to operate, larynx/hypopharynx I don’t want to operate, oropharynx, which is where HPV, that’s the majority of our patients, very long conversations about surgery/no surgery. And this is where we’ll talk later also maybe about de-escalation in the HPV patients and how we think about de-escalation.

DR LOVE: So I don’t think you’re going to hear a more interesting set of cases than you will here today. It’s amazing how you tackle these complicated not only medical but biopsychosocial issues. And Lynsey, we’re going to start out in a second with your 62-year-old man. Again, I don’t think you’ll hear a story like this in any other cancer.

But just to pick up, though, on the really important issue, getting back to you, Bob. Robert mentioned de-escalation with HPV. Can you talk a little bit about the difference? You talked about 2 different types but also the difference in the aggressiveness and the approach to therapy based on the two.

DR FERRIS: Yeah. It’s a really key factor because as Robert mentioned we have different treatments for the HPV-positive. You can see that oropharynx. And although it shows that the oropharynx, that tonsil and base of tongue, can have both HPV-positive and HPV-negative, in Western countries it’s honestly 80%, sometimes 90% HPV-positive, so it’s really been this bizarre transition over 30 or 40 years for somewhat unexplained reasons, but the survival is dramatically different. So the HPV-negative patients, the traditional tobacco carcinogen type, have really not had any improvement in survival in decades. It’s around 40% to 50%. Leaving aside all of the toxicities of that we really only cure half or a bit less.

On the other hand, this new type of head and neck cancer, the HPV-positive, we began to recognize that patients were surviving longer, in the 90s, and then it turned out there was an increasing fraction that were HPV-positive. So that survival is in the 80% to 90% in long term. So when we talk about the different treatments they can all achieve the high survival with HPV-positive head and neck cancers, and almost no matter what we throw at HPV-negative cancers we’ve not been able to really make a major impact.

And so we can talk about some of the newer therapies that hold promise for that very difficult to cure HPV-negative disease, but as Neil mentioned the challenge when you have an 80% to 90% survival, although we want to recognize that we still don’t cure 10% to 15%, but the challenge then becomes how can you maintain that great survival but with less toxicity because the more you cure somebody then they’ve got decades to live with the side effects of achieving that great cure. And so for the past 10 to 15 years all of the prospective clinical trials have been asking can we back off a little bit on the radiation, perhaps 50 Gy instead of 60 Gy? Can we change chemotherapy from a high dose every 3 weeks to a more lower dose weekly? So de-escalation.

And then of course surgery sometimes gets a bad name because of what we used to do in the 80s and 90s, but in 2009 a robotic surgical technique was approved, it’s called transoral robotic surgery, where we can use a surgical robot to get back to the tonsil area, which is hard to see without magnified, angled telescopes and articulated robotic instruments. So we use robotic surgery to hopefully de-intensify the really drastic surgical procedures that it took to get way back in the back of the throat.

DR LOVE: So one more question before we get back to the case. It’s just so fun to pick these people’s brains. But Robert, I was flashing on immunotherapy was just coming. It wasn’t that long ago, like 10 years ago, and I was doing — we were doing a program with a very prominent head and neck person, and I was thinking to myself that was, again, when HPV was coming out, so now we were seeing 2 different ways that people are kind of getting there. And I remember asking, because this was even before the studies of immunotherapy, like does immunotherapy work better in one or the other, does it work better in the viral patients. That would make sense. Does it work better in the smokers? We see that in lung cancer. And at that point the doc said, “I don’t think there’s much of a difference.” Is that still the case?

DR HADDAD: Yeah. I mean immunotherapy current is primarily used in incurable setting, so when the cancer comes back. And it has profoundly changed and altered the outcome for these patients. It’s really been a great addition to the treatment for the patients with recurrent disease. It does work for both. And actually you find studies where it seems to work a little bit less in the HPV … the checkpoint inhibitors in particular. And there are other studies that show that if you combine the checkpoint inhibitors with chemotherapy you actually augment the response quite a bit.

So as of now, this is an area of active investigation as we try to bring those drugs to the curative setting to give them, for example, before surgery in a curative intent setting. And those are all research trials, so we don’t recommend that those are used in the clinical practice for those patients. But in the recurrent and metastatic setting these have now become the standard of care. And they have profoundly altered survival, and patients are living longer because of the checkpoint inhibitors for sure.

DR LOVE: But again, a cancer cell that’s gotten to be cancer because of HPV or smoking still either way is going to respond to immunotherapy similarly?

DR HADDAD: Yes. Also, I mean, the question you’re raising, Neil, brings up the question also of targeting HPV in particular. And that’s an area that has been very, very challenging but of active investigation. And if you noticed yesterday ASCO released their abstract for this meeting, and I you look at the head and neck oral session there are actually 3 presentations about anti-HPV therapies in recurrent metastatic disease.

DR LOVE: Wow.

DR HADDAD: The results are not released. They’re embargoed by ASCO. But just to give you a sense that in 1 oral session out of 9 presentations there will be 3 about HPV-directed therapies in recurrent metastatic disease. So obviously for HPV if we all agree that we’re going to vaccinate everybody at a young age we would not have this conversation; hopefully there’d be less head and neck cancer. But that’s for another day.

But one big area of investigation is targeting HPV virus, because if you can do that not only you will actually be able to treat head and neck cancer, cervical cancer is HPV related, anal cancer is HPV related, so it becomes really a big deal. But that has —

DR LOVE: Like antivirals?

DR HADDAD: Antivirals.

DR LOVE: Antivirals.

DR HADDAD: We don’t have them.

DR LOVE: Wow. Wow. Okay.

DR HADDAD: We need them.

DR LOVE: But these things at ASCO, are they antivirals or some other strategy?

DR HADDAD: No. They’re other strategies.

DR LOVE: Huh. Interesting. Wow. Interesting.

Okay. Let’s get back to the reality we call “the real world,” so to speak. What an interesting case, this 62-year-old man, Lynsey. What happened with him?

MS TEULINGS: Yeah. So this case highlights the importance of stigma in head and neck cancer, and I’d like to point out that we’ve talked a lot about the causes of HPV and them being associated with lifestyle factors, risky lifestyle factors such as HPV, tobacco and alcohol. So there’s a lot of stigma associated with these diagnoses, and it’s something that we often have to address at the first meeting with the patient.

But there’s also stigma associated with the treatment and outcomes from this cancer. So my colleagues here have highlighted that the outcomes of treatment can be very disfiguring for patients. Some patients lose their ability to speak, their ability to eat, which are really important social — ways that patients interact socially after treatment, so there’s a lot of stigma in general associated with the diagnosis.

But this case highlights the HPV-related stigma. So it was a patient of mine who had an HPV-related cancer, and at the first meeting with him he brought his significant other, his spouse of many years. And the diagnosis was presented to the patient and the wife, and as with many discussions like this there’s a lot of questions that come up. How did I get this cancer? Was this my fault? Could this have been avoided? Who gave it to who? Is the spouse at risk for cancer because the patient has it? What does this mean for me? What does this mean for my significant other?

So the education surrounding this. I like to tell patients human papillomavirus is a very common sexually transmitted disease. It occurs in about 80% of people who’ve been sexually active at some point in their lifetime. There’s only certain high-risk HPV that will later go on to cause cancer, and there’s no way of knowing at the time of exposure. Unless you’re a woman who gets high-risk HPV identified on a Pap smear there’s often no way of knowing what HPV you’ve been exposed to. And so I do a lot of counseling with patients that this is very normal.

But unfortunately this patient’s spouse really could not wrap her head around it, and no matter what counseling you do sometimes it doesn’t sink in, and they want to hear what they want to hear. But the patient’s spouse unfortunately decided to divorce the patient while undergoing treatment thinking that the HPV must have been contracted at some point during their marriage through infidelity.

So that was a very, very difficult case. I think it’s an extreme example. I don’t often see this, but it does happen, and it’s important to make sure that you’re providing the right education and then also addressing the psychosocial and emotional distress that goes along with these types of diagnoses.

DR LOVE: So I’m curious about the follow-up and the current status of the patient. Last night we were talking about burnout, trying to avoid burnout, but the other thing is being inspired by your patients who — can you imagine what it feels like to be in the middle of treatment and have this experience and then to be able to overcome it. And to be part of that with the patient is such a privilege in oncology. What happened?

MS TEULINGS: So the patient’s doing great now. He’s about 2 years out. He’s had a complete response to therapy, and he’s recovered very well from the chemoradiation that he received.

From a social standpoint he’s moved to Florida. He’s very happy. He’s still very close with his children and has really no contact with his ex-wife, but I think retrospectively he kind of realized that maybe his marriage was heading in this direction before the diagnosis, and that was kind of the tipping point.

But I just wanted to go back and address one more thing that I like to talk to patients in terms of HPV. And it’s important to let them know that while the cancer is not transmissible the virus is, but it’s often that we expect that both partners have been exposed already. So.

Ongoing Screening and Prevention After Potentially Curative Therapy for Head and Neck Cancer

DR LOVE: So Bob, any thoughts, maybe in terms of these kinds of situations, the HPV scenario?

DR FERRIS: Actually, I was going to jump in. I wanted Lynsey to finish because it’s really such a compelling story. But I’d say all 4 of us here who deal with head and neck cancer patients, and we use the word epidemic of HPV, have our own rap, our own sort of stories and interactions and the way we lay it out to our patients. It is a sexually transmitted disease, but I don’t personally use that terminology. I say normal human behavior. I don’t think any of us would be here in the room without the normal human behavior that I think patients need to understand. And as Lynsey brought up we’ve all had the spouse, not maybe to the extreme outcome as she described, but more often than not you can see it in their eyes when the spouse is there, and they’re looking at each other, where’d this come from, and they’re kind of rewinding the clock.

And so I know Robert and Meetal will have other comments, but we try to put it on the table. I just from the beginning say it. I have some advantage because my mother-in-law is 16 years out from an HPV-related head and neck cancer, and it allows me to tell them about discussions. It was pretty funny because she was so proud she didn’t have a tobacco-related cancer because she had been a smoker, and then I had to kind of explain to her, and then she said, “Oh.”

But if you kind of reduce some of the stigma and say look, every one of us is exposed to human papillomavirus through normal human behavior, and there is a very good reason to think that this was just transmitted. In fact, if you were to be a laboratory person you could probably, I don’t want to make anyone crazy here, find HPV on things that we touch every day. It doesn’t necessarily mean there was some infidelity or anything like that.

So again, on the continuum of the discussions we face this is one that comes up very frequently with the virus, and so it is important to kind of have your own story to reduce the intensity of that. And then the good news is the survival is very high so you can pivot pretty quickly into getting rid of it.

DR LOVE: You were saying you have a survival clinic there?

DR FERRIS: We have a survivorship clinic when the survival is 80% to 90%. In some of our clinical trials for the low tumor volume, never smoker, we are able to get 90% to 95% survival. And then the cancer, I should have pointed out, the HPV-positive one, tends to occur 6 or 8 years earlier, so a 50-year-old instead of a 60-year-old. So then they’ve got 40 or 50 years to live, we call that survivorship. And so all of the swallowing difficulties, some of the effects of surgery or radiation that we call the — put them into a new normal some months or years afterwards. We have begun to realize there is biobehavioral, psychosocial, speech and swallowing therapy, there’s all kinds of aspects, that up until 10 or 15 years ago we were confronting as the treating physicians and nurses, but trying to coordinate outside of the busy clinic, get them over to dental for radiation-induced aspects or a speech and swallowing therapist on a different visit.

We now very early on, almost at diagnosis, begin with swallowing therapy because no matter what choices — and Dr Haddad and I can arm wrestle about the toxicity coming from surgery or radiation, we can tease each other as we have for decades working together in sessions like this. But the fact is no matter what treatment you choose it’s going to impact on the survivorship. And that survivorship is almost guaranteed when the survival rate is 90%. So we start very early, make sure they swallow right through treatment, even if the radiation took away their ability to taste. And I tell them eating is like I wrote a prescription, do this medicine 3 times a day. Well, you’ve got to keep your weight up, keep your immune system stable to be able to get through that 6 to 8 weeks of treatment.

So we start survivorship at diagnosis, and then really help them be prepared for what’s to come. But there is still an aspect that we don’t understand, is some folks sail through their radiation and chemo, other folks are absolutely debilitated, and they get edema, woody stiff neck. And so we have to personalize it, and a dedicated survivorship clinic is really key to that.

DR LOVE: That’s such a fantastic idea. In a second, Ms Dharia, I’d like you to tell us kind of another kind of scenario in your 56-year-old man. But first just to come back to you, Robert, in thinking about following these patients long term how much of a concern is a second head and neck cancer? I would imagine that might get integrated into this survivorship approach. And can you talk a little bit about your 45-year-old man who had HPV oropharyngeal cancer. But first what about second cancers?

DR HADDAD: Yeah. So I just want to close the loop on the previous conversation. Because these patients, they tend to be younger than the smoking-related head and neck cancers, so they’re usually in the 45 to 55 age group, which means most of them will have children that are less than 26 years old, so this is always an opportunity for us to talk to patients and their spouses about vaccinating their children. And that comes often in the conversation from patients or the spouse, I have a 14-year-old, I have a 15-year-old, because not everyone unfortunately knows about HPV vaccination. So it’s an opportunity to open that conversation with the patient and their spouse to think about vaccinating their children. That’s really important.

Also what has become available in the past 5 years that we didn’t have before is now we can measure HPV DNA in the blood. So just like we all know about PSA, right? We all know that you can measure PSA for screening for prostate cancer. There is a test that is so much better than PSA actually that most people don’t know about, and that’s HPV DNA. It’s a blood test that you can use to measure HPV DNA in the blood, and it’s an HPV that’s specific to cancer.

So we use that test now routinely in our clinic in patients treated for head and neck cancer, and we follow them, and we see those factors go down to undetectable from a titer that’s pretreatment, and we want it to stay undetectable. So keep that in mind as you —

DR LOVE: You’re saying the HPV goes down from like chemoradiation as you —

DR HADDAD: Correct. Correct. So that’s a marker of response.

DR LOVE: Really?

DR HADDAD: And if the number it goes down to zero and then starts creeping up that patient will have recurrent disease. It’s so much more specific —

DR LOVE: Wow.

DR HADDAD: — than PSA.

DR LOVE: Or MRD. We’re going to talk about that tomorrow night.

DR HADDAD: So that’s something that’s coming next.

DR LOVE: I did not know about it. I’ve never heard about that. That’s incredible.

DR FERRIS: Neil told us to generate any arguments where possible.

DR LOVE: Okay, yeah.

DR FERRIS: So I’m going to tell you, in Pittsburgh we do not do what Dr Haddad is telling you to do. In our practice it has not been subjected to prospective clinical trials, and when you have a 90% survival you don’t have to have an HPV test. It’s always going to go to zero because you were going to cure them all along. So I would just point out it is an expensive test, and I do think it needs prospective trials before using it in standard practice.

DR LOVE: Interesting. We always like a little controversy here.

Radiation Therapy and Chemotherapy Side Effects

DR LOVE: Let’s hear about this 56-year-old man, really an incredible story here, Ms Dharia.

MS DHARIA: Yeah. So coming back to chemoradiation and cure, this was a 56-year-old male who had squamous cell carcinoma of the base of tongue. And he had undergone a resection, and his pathology had shown high-risk features, which are extranodal extension and positive margins, so the next step in treatment was definitive radiation with chemotherapy. And for any staff nurses out there, this particular treatment, as has already been said by our panel, is extremely tough, and one of the biggest struggles is to make sure that these patients have adequate nutrition. So it’s very important that we refer these patients early to a dietician, really actually on diagnosis, and so a dietician can meet with the patient weekly to watch the patient’s weight and to make suggestions on how they can increase calorie intake and protein intake.

It’s also very important that patients understand the complications that can occur from malnutrition, and malnutrition in head and neck patients is linked to increased morbidity and mortality. It’s increased to treatment interruptions, hospitalizations, increased treatment toxicity, which is a really important one, depression, decreased physical activity and overall decreased quality of life. So going through that with most patients they realize the importance of seeing the dietician and making sure that their nutrition is adequate.

It's quite a challenge because during radiation/chemotherapy a lot of patients will experience mucositis, and this is quite common, and so it becomes very painful for patients to even put food in their mouth or to swallow. And so we usually make sure that patients are scheduled for hydration twice a week on top of their chemotherapy to make sure that they’re getting adequate hydration. But we also send them back to the dietician to say well what kinds of changes do we need to make to their diet so that it’s easier for them to take in food. And that might mean switching from solid foods to semi-solid foods and then eventually just liquid nutrition.

Patients can also suffer from dry mouth and also taste changes. And this particular case is quite unique because the gentleman that I saw was basically morbidly obese for almost 20 years before he was diagnosed with head and neck cancer. The majority of patients that we see with head and neck cancer that come to the clinic are usually losing weight, they’re already malnourished, and this patient was morbidly obese.

So when I went to see this patient on week 3 of treatment one of the infusion nurses said to me, “Isn’t it great he’s lost 8% of his body weight? He can finally fit into the infusion chair. He’s not huffing and puffing. His blood pressure is perfect. He no longer needs to take antihypertensives. He says he feels great.” And I thought oh my goodness, he’s lost 8% of his body weight, and a lot of that had come from muscle loss. It’s very dangerous.

So when I went over to the patient I thought my goodness, I’ve really got a challenge on my hands because this gentleman has been trying to lose weight for 20 years, and I’m there trying to tell him not to lose anymore weight. I thought I’ve really got a fight on my hands. So I sat next to him, and I said, “I heard you’ve been losing weight.” And he said, “Yes. It’s great. Finally, after 20 years of trying, I’m finally able to lose the weight.” And he said it was awful being obese. He said he’d restricted himself socially. He felt socially isolated. He’d suffered from depression. So there were all sorts of factors that had occurred secondary to his perceptions of his body image.

So I did say to him, “Malnutrition is not great. It’s linked to all the things that I said it was.” And actually he didn’t heed my advice, and 3 days later he was hospitalized. He was just very, very weak and fatigued.

But one of the things I want to bring up about this particular scenario is that this patient had used food for a very long time as a coping mechanism with his stresses in life. And because he experienced taste changes, he actually said everything tasted like cardboard, his comfort blanket had been removed. And there he was dealing with cancer, dealing with a very difficult treatment with no coping mechanism in place.

And so I think it’s really important to assess our patients from the get-go to ask them is food part of your coping mechanism because they do lose their ability to taste food or they can’t swallow, they can’t take in nutrition. They’ve lost a form of comfort, and we need to make sure that these patients are seeing a therapist quite early on so that they can learn new coping mechanisms and receive support until that’s in place.

DR LOVE: Robert?

DR FERRIS: Yeah. So, I mean, this is a great case because it really highlights a number of issues. In the past when I started doing this, like 15 or 20 years ago, we used to put feeding tubes in every patient. And we have moved away from this, but I think we have moved away to the other extreme where we now try not to put it in anybody. And really it’s key. What I do in my practice is I always introduce the idea of the feeding tube to the patient as we are designing their treatment first so that when this comes up during treatment it’s not, “Why are you telling me about this now for the first time?”

A good number of head and neck cancer patients will require a feeding tube to get through the treatment, and really it’s not an invasive procedure. We explain to the patients early on this is a temporary measure that’s going to make the treatment 10 times easier for you and allow you to finish the treatment on time.

One of the key measures of success of head and neck cancer treatment is not to interrupt treatment, and if you have to interrupt your treatment because of malnutrition that becomes a problem, and cure rates go down. So I would again encourage everybody to introduce the notion, not to put the feeding tube in up front but to introduce the notion to the patient early on in the disease course that you might require a feeding tube to get through treatment. Patients who have big-volume disease, where you have to treat bilateral neck, they often will need a feeding tube to get through the treatment because of severe mucositis and inability to swallow. So nutrition is really key to get through head and neck cancer, and a feeding tube can be extremely helpful.

And I’ll tell you in my practice of 23 years I’ve not had any patients who’ve become feeding tube dependent after treatment. We always can get them out later. So it’s not a permanent feeding tube. Number 1.

Number 2, the issue about what we discussed in the beginning of this conversation about that early assessment of the patient. Chemoradiation is not for everybody. It is one of the most grueling, aggressive, intense treatment we give in any solid tumor; so assessing the patient before they start treatment, including their social support. Is there someone to bring them back and forth 7 weeks of radiation infusion — to radiation treatment? What happens after they finish chemoradiation? Do they have someone with them? You can’t give head and neck cancer treatment to someone with no social support. They will not be able to go through it, and they will likely die from the treatment.

So you often have to really modify what you’re doing based on the patient in front of you and what social support system they have. But also that first visit opportunity to rally the troops. Who are your neighbors? Do you have a cousin? An uncle? An aunt? Your son lives in Florida, can they move in here?

And that applies also for surgery. We see a lot of patients now in their 70s and 80s. We have an aging patient population with head and neck cancer. In talking to those patients about the laryngectomy, for example, or a glossectomy, it really borders sometimes on unethical behavior.

So we have to get those patients through geriatric assessment first looking at can they undergo the operation and heal from it. Because yes, we can do the surgery and have the patient in the Brigham inpatient service for 2 weeks, but then what? They’re going to go home. They have a flap. They had a neck dissection done. They need post radiation. Can they do this? So having that. We spoke about the small village to take care of these patients. You need those types of assessments before you implement your treatment.

This is not a cookbook surgery, radiation/chemo for everybody. No, it’s not. These are very tough treatments.

The Potential Short- and Long-Term Effects of Surgery for Head and Neck Cancer

DR LOVE: So Bob, I know you had a couple of thoughts, and also just to round this out I’d like to hear about your 65-year-old man with laryngeal cancer, but first your thoughts.

DR FERRIS: Well, I think Robert really nicely pointed it out, and I completely agree with everything you said, so you can see we agree on many things.

DR LOVE: You’re friends again?

DR FERRIS: As long as we don’t talk about the Patriots and Steelers, then we’re going to get along great.

But what he did point out is that oftentimes a good multidisciplinary treatment team, the surgeon is trying to see if there is a nonsurgical therapy that’s best because of our mutual respect. Medical and radiation oncologists send them over and say is there anything we can do surgically, because I think we all recognize that the tools we currently have impair on speaking and swallowing.

And the point about a feeding tube is an important one. We, as they do in Boston, try to really avoid it. But certainly when you get somebody who is 20 and 30 and sometimes 40 pounds down from their fighting weight, as we say, when they walked in the clinic, it’s not going to really mount the best response to therapy. And then, as Dr Haddad mentioned, a break is the worst thing that can happen. So it’s a great idea to let them know that this sometimes happens, but the way to really help avoiding it is to get them with a speech and swallowing therapist, to have supportive care. Sometimes we feel like cheerleaders, and that’s okay, to get them through it and avoid that tube.

So I think it’s really important because — for 2 reasons. Number 1, no treatment breaks. But number 2, your best chance to swallow long term is if you don’t stop swallowing through therapy. And that’s why we don’t want it to be a crutch or a substitute, but it’s a supplement to just get a Boost or an Ensure in there once or twice a day even if they’re swallowing. So I would point that out.

And we’ve been talking about oropharynx cancer, but this other case is larynx cancer, which is the other subsite that has the HPV-negative disease, not as great survival. And we really went through in the 90s this organ preservation where we were removing someone’s larynx pretty much as the standard approach, and then we would find out after the laryngectomy and the neck dissections where we removed the lymph nodes, do they need radiation, do they need chemo and radiation.

And the recognition was that you could actually put chemo and radiation up front, hold surgery in reserve, and about half of the time, 50% to 60% of the time, allow somebody to, as Robert called it maintain the organ, we call it organ preservation, nonsurgical therapy. The problem with it is that everybody up front thinks they will be in that 50% to 60%, and so we have to really counsel them. It’s extraordinarily hard.

I frequently get a surgical consent, and the most interesting surgical consents are with the trial lawyers because I usually say sign here, and then they say, “Oh, don’t worry about it.” And I say, “No, let me go through all of the side effects, and let me lay it out.” And they say, “Oh, I’ve seen this before.” And it’s hard to really tell somebody what they’re going to experience in a clinic visit, even a good hour long, or in a surgical consent.

So the larynx cancer in this particular patient who is a 65-year-old who had an intermediate to semibulky tumor but still had a pretty functional larynx, was able to speak and swallow, had neck disease. That’s a classic patient where we want to avoid removing the larynx, removing the voice box, where they have to speak and breathe through a stoma in the neck. And there’s stigma attached to that. For instance, we want everybody to stop smoking, but we put these commercials on with the older gentleman who had the stoma, and so on. And I go to the Panera nearby us, and there’s a guy there playing cards with his friends, and you do have a life after laryngectomy, but we want to avoid it.

So in this particular patient we used a chemo and radiation option up front. It usually works well, and then the problem is that 9 months or 12 months in that other half, where it’s not successful, it comes back. And the problem that we usually have to counsel patients is that then we need a surgical salvage. And the tissues that have been subjected to chemo and radiation don’t heal all that well. There’s often that woody stiff neck of lymphedema. So they’ve got a lot of the side effects.

So we have this balance of counseling separate from all of the dynamics of the HPV-positive/negative in the oropharynx. In the larynx we have I’m going to give this a try, we’ve got about a 50%, 60% chance of preserving your larynx, not that that’s without side effects, but people are willing to tolerate the side effects if they still have their larynx intact. But when they go the route of nonsurgical therapy, and they still need surgery, that’s a tough counseling, and it leads to more supportive care that’s required to allow them to speak and swallow after that.

DR LOVE: So what’s the follow-up with the patient? What’s his current situation?

DR FERRIS: Well, this is not an uncommon situation. I have clinic on Tuesdays, and my surgery day is Thursday, so we had a salvage laryngectomy yesterday actually, a patient like this. On Tuesday we had a series of patients who were doing quite well and were functioning and have a speaking prosthesis that vibrates, and they either have a thumb over the hole or they have a little attachment.

So on the one hand everybody wants to avoid a laryngectomy, and the surgery afterwards usually requires a plastic or reconstructive surgeon to put tissue from elsewhere in the body that was not radiated just to help everything in the neck heal. But we do see life after that laryngectomy, and we have a support group called SPOHNC, which is Society for Patients with Oral and Head and Neck Cancer, and we have a few patients who we can connect prior to treatment with somebody who’s gone through 2 or 3 years later. That’s extraordinarily helpful because they can explain it even better than the physician can.

DR LOVE: Lynsey, any observations on patients post laryngectomy in terms of how they cope?

MS TEULINGS: So I was just going to mention that maybe one of the positives of total laryngectomy after chemoradiation is that it’s a tradeoff between being able to speak and being able to eat. So although patients may be losing their voice box oftentimes if they had a nonfunctional larynx where they were G-tube dependent and aspirating and NPO after total laryngectomy they may be able to swallow again. So it’s a tradeoff.

Emerging Treatment Strategies Aimed at Improving Outcomes Associated with Localized or Locally Advanced Head and Neck Cancer

DR LOVE: So let’s talk about where things may be heading in the future and particularly trying to enhance these patients who are getting chemoradiation therapy, also the development and investigation into a really interesting new mechanism.

Before we get into that, though, just to get back to you, Robert, I was just flashing on the fact that in non-small cell lung cancer they have very good effects using immunotherapy after chemoradiation, durvalumab. That’s now standard of care. More recently we’ve seen it, the same thing, with cervical cancer with pembrolizumab after chemoradiation. And we know that these tumors are very sensitive to immunotherapy, Robert. Are there studies trying to look at adding in immunotherapy to chemoradiation?

DR HADDAD: Yeah. So very active area of investigation. Unfortunately the data so far has not reached the point where we can recommend it. Three weeks ago we presented the first adjuvant immunotherapy trial in the AACR Meeting in San Diego. This was a large, 400-patient study, adjuvant trial, so after chemoradiation randomizing patients to a checkpoint inhibitor or placebo, and the study did not show benefit of the checkpoint inhibitor.

There have also been 3 large, randomized trials adding a checkpoint inhibitor to chemotherapy and radiation therapy. So we’ve been talking about chemoradiation as the backbone of treating head and neck cancer patients. So there have been 3 randomized trials, very large trials, comparing cisplatin/radiation to cisplatin/radiation plus a checkpoint inhibitor. These trials were all negative. They did not reach their primary endpoint of improving outcome.

So the focus now has shifted really to ask the question should we maybe think about intervening earlier than radiation and chemo when the immune milieu is still naïve and is still intact. So what you will — what you are seeing now and what you will see in the next 5 years is a shift in focus into giving a checkpoint inhibitor by itself or in combination prior to definitive treatment, prior to surgery, when the patient has not received any treatment yet.

The initial data that comes from our group and from Bob’s group has shown promise with the checkpoint inhibitors we have in clinic today, but we do not have Phase III studies to support this neoadjuvant intervention, but that’s where I expect you’ll see in the next 5 to 10 years on the immunotherapy aspect. It’s going to be a lot of neoadjuvant. People seem to have I’m going to call it moved away from adding immunotherapy to radiation. That concept might not be the way to go, and intervening earlier might be a better approach. We just have to wait for the studies.

DR LOVE: So Bob, of course we’re seeing more and more targeted therapies in oncology. I’m really fascinated by this apoptosis strategy. It’s kind of challenging to pronounce, but xevinapant. But can you talk a little bit about your vision about what apoptosis is, what this agent is, and where you see it heading?

DR FERRIS: Sure, yeah. So apoptosis is a word that means tumor cell death or any cell death. And normal cells grow and die. That’s kind of the normal life cycle of any normal cell in our body. It has a certain lifespan. The problem with tumor cells is they don’t die, particularly when we want them to. That’s the effect of chemo and radiation. So with surgery you can cut out the tumor cells, chemo and radiation cause tumor cell death, otherwise known as apoptosis.

So tumors that are resistant to chemo and radiation, they develop inhibitors of apoptosis. They want to prevent the effect of chemo and radiation from killing the tumor cell.

And so xevinapant is this drug that is in a class that blocks the inhibitors, so it promotes tumor cell death. It inhibits the inhibitors. And so the advantage of that is obviously it intensifies the benefit of chemo and radiation in killing the cancer cells, and it may do so in a way that the cell death is now more recognizable to the immune system because there’s a certain type of cell death which happens in our body all the time which is just the normal sequence. You don’t want your immune system to recognize them, but then there are also other danger signals of abnormal cells, and you do want your immune system to recognize those. So we think drugs like xevinapant, which promote tumor cell death, enhance the effect of chemo and radiation.

And there was a very impressive Phase II trial adding xevinapant on top of chemo and radiation that had a really dramatic benefit, and so there are Phase III trials to confirm that. And if this were to come to pass it would really be the first new approval in locally advanced curative patients in decades and would potentially target that HPV-negative subset.

You can see here the old saying is it’s a positive trial if you can put your thumb between the curves. This one, and actually Dr Haddad’s colleague calls this the alligator, when you’ve got a big alligator mouth of the curves being so separated, that we’re really excited about this. And the Phase II trial, again, is being tested in Phase III. It would be something for HPV-negative patients that we haven’t had in decades. And it’s kind of a targeted therapy because it reverses some of the strategies that tumors have to avoid the chemo and radiation.

DR LOVE: So the prostate cancer people have a trial, and they call it the pelican graph.

DR FERRIS: Yeah.

DR LOVE: Because they want the pelican to open their mouth. The top line is the patients who were treated that you see the risk of relapse is much — the risk of remaining without relapse much higher.

Also, we were talking about hazard rate. And if you look down there at the bottom hazard rate of 0.33. When you see a hazard rate in a trial with a curve like that what you — you subtract 33 from 100, and what you say is the chance of relapse has been reduced by 67%. So if your hazard rate is 0.33, am I correct?

DR FERRIS: 100%.

DR LOVE: At any point in time there’s a two thirds chance, better chance the patient’s not going to be relapsing at any point in these curves. That’s a very impressive hazard rate. Whether that’s going to hold up in the Phase III trial. That’s going to have more patients and more ability to define that.

Robert, any thoughts about this fascinating agent? And also the other apoptotic thing we’ve been hearing about for years is venetoclax. We were talking about that last night with CLL, obviously AML. That also hits the apoptotic cycle, I think, so to speak. What’s the difference between xevinapant and venetoclax, Robert?

DR HADDAD: This particular agent, xevinapant, is the most mature in head and neck cancer. The Phase III actually is complete. It’s done. The results are expected shortly. And as Bob mentioned, if this data that you’re seeing here is going to pan out in the Phase III this would be the first improvement in treating head and neck cancer that we’ve seen for a very, very long time. But again, we all understand the caveat of Phase II data and the need to replicate it in Phase III. But the Phase III is done, it’s complete, so we should know shortly whether this would be a new treatment for our patients.

I would also mention this is an oral drug. This is not an intravenous infusion. This is a drug that is oral. And the studies in this particular agent were done with high-dose bolus cisplatinum not the weekly cisplatinum that is currently in use. So we will know later.

The other agents. I’m not working with any other inhibitor of apoptosis. This is an agent I’ve been working with now for many years, and the one, as I said, that is the most mature. There are others in earlier stages of development, but we’re not working with those.

DR LOVE: I mean, this may be a naïve question, but how does this strategy compare to venetoclax? I mean I know it’s working on the same system. Is it a different way.

DR HADDAD: Yeah. I don’t know. I really don’t know how they are different. I don’t know Bob if you do.

DR FERRIS: I think it goes back to there are 2 pathways to cell death called the classical and nonclassical.

DR LOVE: Right.

DR FERRIS: And as Robert was mentioning earlier the nonclassical one that this hits also has kind of an inflammatory side benefit that’s called the NF-κB pathway, and so that’s where you may have not just tumor cell death but good, we say “good” inflammation where the immune system gets drawn in, and that’s the classical/nonclassical cell death pathway.

Tolerability Considerations with Xevinapant

DR LOVE: So I’d like to hear about a couple of patients who actually got this therapy. Robert, you have a 55-year-old man who got xevinapant plus chemoradiation. What happened with him? And I guess you have to separate out side effects from chemoradiation from this drug. What kind of side effects or toxicity does this have?

DR HADDAD: Yeah. So remember the concept with this agent is — everything we spent talking about in the first part of the session today is dose de-escalation. Here now we’re talking dose escalation. And why are we doing this? Because as we had said, HPV-positive patients they do very well. 90% cure average. HPV-negative they don’t do so well. Cure rate’s 50%. So the question there is, we need to do better than 50%. How do we do better? So the concept is should we add to chemoradiation.

So the first attempt was immunotherapy. All the trials have been negative, so adding checkpoint inhibition to chemotherapy/RT does not improve outcome. That’s another attempt now of dose escalation by adding an inhibitor of an inhibitor of apoptosis to chemoradiation. So it’s a dose escalation strategy building on cisplatin/radiation by adding a third agent.

What happens when you do this? This potentially is a radiosensitizer, so when you add to radiation and chemo potentially — again, we don’t have the data set yet because this Phase III is complete but we don’t have the results, and it’s a placebo control, so I don’t know what my patients are getting to really make that judgment. But we expect and we might predict that when you add a radiation sensitizer to a treatment of chemo and radiation the side effects you would experience from chemotherapy and radiation might be exacerbated, mucositis for example, or for example renal toxicity from cisplatinum.

Those are the points we’re going to look for in the Phase III trial. Are we seeing an augmentation of the side effects of chemoradiation, which are quite significant, by adding a third agent to the treatment.

DR LOVE: So I want to hear a little bit more about how this plays out in practice, but I think the fact that you couldn’t tell whether the patient was on a placebo or not is a pretty good sign that maybe it’s not going to be very toxic.

Just in terms of the background, though, Ms Dharia, what are some of the major complications and toxicities that you see with chemoradiation that we’re going to look at at this Phase III trial and see whether they’re — maybe if they’re more intense of not? What are the main issues that you see in these patients?

MS DHARIA: So as stated before mucositis is a major issue, and it can start at the very beginning of treatment. I’ve had patients develop it on week 5 of chemoradiation. It really depends. If they’re getting a higher dose of cisplatin at the 100 mg/m², which is done every 3 weeks, when the mucositis starts it can get really out of hand because you’ve got a bigger dose at that point sensitizing the tissues.

So mucositis is usually treated — well, we usually help to ameliorate the symptoms by using viscus lidocaine to try and numb the area and also using analgesics.

Other complications from radiation/chemotherapy include problems with swallowing, painful swallowing, changes in taste, dry mouth, also renal impairment from cisplatin, getting nephrotoxicity, ototoxicity from the cisplatin treatment. So we usually send patients to audiology at baseline so we have an idea of where they’re starting from. Nausea and vomiting is a major issue with cisplatin chemotherapy, so we make sure patients have adequate antiemetics at home and are also on aprepitant or rolapitant with the cisplatin treatment.

DR LOVE: What do you tell your patients in general, I’m sure it’s very variable, in terms of how long it takes to get back to where they were before?

MS DHARIA: It really varies. I’m very careful about that answer because I have patients who ask me well when’s my taste going to come back. That seems to be the most common question. And I’ve had patients who still 8 months after chemotherapy everything tastes like garbage, so for those patients nutrition is really, really tough.

DR LOVE: So that’s the background on which this new agent is being placed so to speak, Robert, and obviously at this point the only patients we’re going to know about are on trial since it’s not an approved agent. What happened with your 55-year-old man, Robert?

DR HADDAD: Oh. He completed treatment more than a year ago now, complete remission, no relapse so far and doing great. So uneventful.

DR LOVE: What did he experience when he went through chemoradiation?

DR HADDAD: He did require a feeding tube to get through the treatment. The feeding tube was removed around week 8 post-treatment. Remember, staging for these patients typically occurs around 3 months after treatment. You have to wait for the inflammation to resolve before you image them. He recovered his taste. He’s back to work full time doing great.

DR LOVE: Great. And also, Bob, you had a patient also who received — or was on a trial, a 67-year-old woman. What happened with her?

DR FERRIS: Yeah. I think this has been pointed out. One of the nice things about this particular drug is that the toxicities that we see are those that are expected, that are known. There’s not new signals or new toxicities. We went through that for 10 years or so when the immunotherapies came out. We had to learn about a whole new class of side effects from the PD-1 inhibitors, which was fun. It was an interesting deviation to learn about, but it’s nice to come back to an agent that may slightly intensify some of the side effects, but they’re all known ones. We’ve built our expertise and our interventions around recognizing them and reducing them. So the dry mouth and the mucositis all of that the xevinapant seems to just kind of perhaps amplify a little bit, but again, nothing off the farm or something that we have to now built up a lot of new expertise. So that’s what we generally see.

And I would point out there is some thought as all of us age over age 70 we don’t usually — our medical oncologists here can comment, but we don’t want to give them traditional cisplatin chemotherapy despite it being effective and the standard of care, and xevinapant may be good with radiation as a replacement for chemotherapy. So I think there’s a number of ways as a radiosensitizer or some side effect — or radiation intensifier that xevinapant may come in to replace chemo as well.

DR LOVE: Wow. That could make a pretty big difference in quality of life, I would think.

This is interesting. I love the pictures here too. I always liked Future Oncology. It’s a great journal if you want to check it out.

But this is a Phase II trial. Typically when we do research, Phase I they kind of figure out what the right dose is, what the toxicity is. Phase II they’ll do a randomized study, a comparative study, but then you need not as many patients. But then if that’s positive then you do a Phase III, much bigger, much more specific, where you can get a lot better information on efficacy and tolerability.

And Lynsey, it kind of looks like you’re not seeing a huge difference, at least in the Phase II. I think people are going to be looking very carefully in the Phase III. Any thoughts about this? And if we could kind of eliminate the chemotherapy and do this agent plus radiation therapy any thoughts about how that might alter the patient’s course?

MS TEULINGS: I think someone else also pointed this out, but I think it’s important to recognize that this study was done with higher doses of cisplatin, so 100 mg/m² given 3 times through the 7-week course of chemoradiation. At Yale, and I think in many other practices, we’ve moved towards more of giving a weekly dose of cisplatin, which is 40 mg/m², because the outcomes in studies have suggested that it’s the same but a little less toxic.

So I don’t know much about the Phase III trial. I’m hoping they took that into consideration and have tested it with the weekly regimen so that we actually have a sense of the differences in toxicity. Because I do think the large dose of cisplatin versus the weekly dose can change, particularly when you’re thinking about things like renal function, there’s differences in side effects for sure.

DR LOVE: So I’m a big fan of cool clinical trial names, and I love this one. XRAY VISION. Some of my favorites are — I love the GLOW trial, and there are a couple of GLOW trials. But anyhow, Robert, can you talk about what you’re going to be looking at in the Phase III trial?

DR HADDAD: So this is a trial that was designed for patients who are not eligible to receive cisplatin, so this is for cisplatinum-ineligible patients. So think of the patient that has hearing loss, that has neuropathy, that has nephropathy, where you could not give them cisplatinum-based therapy. So the randomization here is between radiation/xevinapant versus radiation/placebo. So a straightforward design specifically focused on those patients who are not eligible to receive cisplatinum. It’s a Phase III registrational trial. Bob is the principal investigator of this trial. So it’s ongoing, and it’s going to take some time to finish because it launched last year.

DR LOVE: So what do we know at this point, Bob, in terms of tolerability of this regimen compared to say traditional chemoradiation?

DR FERRIS: I think one thing to point out from that prior slide is that all of the side effects are recognized and expected, and we manage them with chemo and radiation. The big, highlighted numbers you’re showing are true, but the smaller numbers are really severe toxicities. Did it increase the Grade 3 and Grade 4? Those tend to be ones that may cause a need to be treatment reduction or a break, and that is almost exactly the same. So yes there may be 35 versus 26, but those tend to be manageable, so that’s the nice thing is you can intensify the effect on the tumor of the chemo and the radiation with really less collateral damage, and I think that’s our hope to see this when it pans out.

DR LOVE: What have you actually observed in patients? Does it seem better tolerated than chemoradiation?

DR FERRIS: We don’t always know who’s on the placebo.

DR LOVE: Right.

DR FERRIS: And because there’s enough heterogeneity in —

DR LOVE: We’ll have to wait for the trial.

DR FERRIS: Yeah.

The Established Role of Anti-PD-1/PD-L1 Antibodies in Therapy for Advanced Head and Neck Cancer

DR LOVE: All right. Well, I want to also talk about immunotherapy. We’ve alluded to that, as well, and of course obviously throughout oncology we see that. Robert, can you kind of summarize where we are in terms of immunotherapy with head and neck cancer and where you see things heading?

DR HADDAD: So we have 2 — we have actually 3 agents now approved in head and neck cancer immunotherapy. Pembrolizumab is approved in the first-line treatment for patients with recurrent and metastatic disease as a single agent for patients with a CPS-positive score, so any CPS of 1 or more recurrent metastatic first-line pembro as single agent. Also pembro plus chemotherapy, a platinum/5-FU, is also approved for all comers with head and neck cancer patients and recurrent metastatic. The other agent that’s approved based on the CheckMate 141 study that Bob and I were involved in is nivolumab as a single agent, also for patients with recurrent head and neck cancer that have been exposed to platinum.

So we have now in the clinic 2 checkpoint inhibitors for patients with recurrent metastatic disease. And as I had said earlier these agents profoundly impact survival. They don’t work in everybody, the response rate’s around 20%, but when they work you see a durable response, a profound response. And we actually can talk about cure also for some of these patients. I’ve had a number of patients now that have gotten to 2 years’ treatment, complete response, stop treatment, cancer doesn’t come back. So it’s a reality now that these drugs are impacting survival and recurrent metastatic disease. We need to do better because most people do not respond. So 20% is not a great number, but it’s a good start.

Newly Approved Immunotherapeutic Strategies for Nasopharyngeal Carcinoma

DR HADDAD: And the third drug that was approved, last year I think, is in nasopharynx cancer, and that is the first drug to be approved in a very, very long time. I don’t think there’s ever been an NPC drug approved in the US. So it’s called toripalimab, and it’s also a PD-1 inhibitor, and that drug is now approved in nasopharyngeal carcinoma, recurrent metastatic disease, with gemcitabine and cisplatinum combination. So it’s a triplet, gem/cis/tori for patients who have metastatic recurrent nasopharyngeal carcinoma in the first-line setting. And also tori is approved as a single agent by itself in recurrent metastatic disease in someone who has been exposed to platinum for the initial treatment.

So in nasopharynx we now have a new checkpoint inhibitor approved. It’s in the clinic. I actually started yesterday my first patient on this drug, a patient from the UAE that came here for treatment with liver metastases nasopharyngeal carcinoma. But also for head and neck cancer we have both pembrolizumab and nivolumab in the clinic.

The future is very bright in immunotherapy. We can spend the next 3 hours talking what’s coming. Things you might have heard of in other diseases like melanoma, like the LAG3s for example, TIM-3s … CD — there’s a lot of agents coming. Also VEGF are coming back. There are a lot of VEGF inhibitors that will be in the clinic. There’s promising Phase II data that’s now going to lead to Phase III data. Also an old class that we’re all familiar with, EGFR, because of cetuximab improvement — approval — indication in head and neck cancer. There are a number of newer EGFR inhibitors that have shown profound activity in Phase II studies that now are moving into Phase III. So I know of at least 2 EGFR inhibitors that will be coming to the clinic in Phase III setting over the next 12 months.

So a big portfolio of new agents coming to the clinic: EGFR, VEGF, immunotherapy. Already we have 3 immunotherapy agents in the clinic.

DR LOVE: So Bob, I’m curious. One of the themes this week is when you have multiple similar agents in the same class. We started out Wednesday night talking about CDK inhibitors in breast cancer. There are 3 of those. There’s a ton of checkpoint inhibitors. They’re not exactly the same. But we also have talked about unless you compare in a trial 2 different things, 2 different treatments, it’s hard to indirectly compare. So want to give us a little lesson in how you put together a checkpoint inhibitor and why toripalimab is different than nivo and pembro, for example?

DR FERRIS: I was afraid you were going to ask me that. I kept thinking Robert’s doing really phenomenal. So I think what we can say without going through the x-ray crystal structures and the binding sites is that the key point of any of these inhibitors is to block the binding of the receptor in the ligand. PD-1 is the receptor. PD-L1 is the ligand. And so you can block that interaction, as shown here in the different colors, with an antibody that binds to different areas of the receptor or the ligand.

What I think is fortunate, the big picture, is that there are many PD-1 inhibitors and a number of companies have developed their own drug, their own antibody that binds as that different colors show, to different parts of the receptor. But the fortunate thing is we’ve seen relatively consistent benefit despite the fact that each of these antibodies may bind to a slightly different area many of them seem to disrupt and prevent the binding of ligand to receptor, and that’s ultimately the key. There’s PD-1 inhibitors from other companies for cutaneous skin squamous cell carcinoma. There’s a series of PD-1 inhibitors. I won’t say that they are replaceable and completely exactly the results, but if you step back from the biological and chemical properties and look at the clinical data in trials they seem to have similar benefits as long as you can disrupt that PD-1/PD-L1 binding interaction.

So although this is approved currently, toripalimab in nasopharyngeal carcinoma, it’s not a very far stretch to run some clinical trials in traditional Western HPV-positive and HPV-negative head and neck cancer and expect it to also work once you have a proof of principle effect.

The Tolerability of Immune Checkpoint Inhibitors

DR LOVE: So Lynsey, of course we talk about checkpoint inhibitors a lot, particularly in solid tumors, and we could spend a lot of time talking about tolerability or toxicity that you see with checkpoint inhibitors, but I’m curious in the patient population of head and neck cancer, any particular considerations. For example in lung cancer people get a little more nervous about pneumonitis because they often have already compromised lungs. When you see a patient who’s on a checkpoint inhibitor with head and neck cancer what are some of the things you’re thinking about? What are you talking to them about?

MS TEULINGS: Sure. So because of the way that checkpoint inhibitors work, by kind of taking the brakes off the patient’s own immune system, it’s really important to counsel patients that the side effects from these medications, or adverse effects I should say, can come from inflammation anywhere in the body. So they’re very different from chemo, and it’s important when you’re starting a medication like this to make sure that patients understand that.

Common side effects of immunotherapy drugs that we see, I would say fatigue and skin toxicity is most common. Severe side effects that I think — that are maybe a little bit more unique to head and neck cancer, that don’t happen often, but one of the things that we see and kind of pay attention to is bleeding risk, fatal bleeding from a major vessel in the neck.

DR LOVE: Interesting. So Robert, here’s a Phase — randomized Phase II study, the JUPITER-02 clinical trial. I would like you to talk a little bit about it, but also because — again, thematically, how to look at a curve like this and figure out what it means.

DR HADDAD: Yeah. So, I mean, this is the study that led to the approval of this agent in the US. The initial data focused on PFS, and this is the final result showing also the OS. And this regimen has 6 cycles of chemo plus immunotherapy, and then you have maintenance immunotherapy, and the other arm had maintenance placebo. So clearly beneficial in PFS and OS endpoints. Again you see the numbers here, 20 months — 21 months versus 8 months, so a clear benefit.

Before this agent actually became available in the US many of us were adding a checkpoint inhibitor to chemotherapy, and we were using the ones that are available in the US, pembrolizumab and nivolumab, because we couldn’t have access to this drug as the drug is not FDA approved. And even those two drugs made it to the NCCN Guidelines. But now that this drug is approved it has become really the de facto standard of care for nasopharyngeal carcinoma in recurrent metastatic setting.

As Bob said, interchangeable. We on the NCCN committee made the decision because we couldn’t have access to this drug, that yes, you can give pembro or nivo with gem/cis. It should be fine. They’re interchangeable. But now that you have this drug approved this is what you should be using in nasopharynx cancer.

DR LOVE: And again, we have emphasized this point all week, the fact that even though you sort of believe they’re all the same you’ve got to go with the trial. This is the trial. Again, getting back to hazard rate, if you look there in the lower right, 0.52, so before it was 0.33. 0.52 still is approximately 50% reduction. So those curves, at any point in time a patient’s on that curve, the chance that they’re going to relapse is 50% less if they got the therapy.

So what about PD-1 levels? A lot of people kind of, Bob, make analogies to lung cancer, smoking, et cetera. And there you see people with high PD-1s who are alive 5 years later, which we never saw in non-small cell lung cancer. What about here? Do you see — I mean, obviously they can be cured, basically, but are you improving the cure rate here?

DR FERRIS: So we test in the tumor with a biopsy for the ligand PD-L1. And you certainly have patients who are PD-L1-negative who you would initially think may not benefit, but they do still benefit. And then you have patients who have high PD-L1, and it’s not a guarantee, but it enriches for the benefit. It enriches for the likelihood of response, and it stacks the deck or enriches for the chance that they will have a better overall survival.

We’ve tried all kinds of different biomarkers to predict who will benefit. PD-L1 is not perfect, but if you do have a PD-L1 level that is high, and we use that combined positive score, or CPS, any positivity we say is CPS 1 or greater. A PD-L1 high is a CPS of 20 or greater. And if you have a PD-L1 CPS 20 or greater you’ve got a substantially better chance to have high overall survival. And you may even be able to get the PD-1 inhibitor without chemotherapy if your PD-L1 level is sufficiently high. So it does come into play for patient selection.

DR LOVE: Yeah. Again, in lung cancer you see people just getting PD-1 and, again, alive 5 years later.

Let’s just close out. Another theme of this meeting is participation in clinical trials, and one of the advantages is to the patient themselves being able to get a therapy that is not available that in this case was proven to be effective and now approved. Robert, you have a 45-year-old man. I guess he was on the study. What happened with him?

DR HADDAD: Yeah. I mean, this is a patient who is on this regimen, and he’s responding to the treatment. Again, we’ve now integrated immunotherapy even before the FDA approval with chemotherapy, so it has become the standard of care.

The next step, what you’re going to see the next 5 years, and they’ll be some ASCO presentations this year, is using these agents in the curative setting. So when you’re giving radiation — remember the treatment for nasopharynx is different because it has induction gem/cis then followed by cis/radiation. So you’re going to see at ASCO some newer data about integrating immunotherapy in the curative treatment of nasopharyngeal carcinoma. All that data come primarily from Sun Yat-sen in China because they see tons of this cancer. It’s very, very common in China, and they can perform Phase III studies, they can do 2 or 3 Phase III studies in 1 year. So it’s not something we can do in the US because this cancer is not very common here, but in China this is a very common cancer, and 90% of the data we have on nasopharynx cancer comes from that institution.

DR LOVE: So I want to thank the faculty. Thank you for attending. Come on back at 12:15 today. We’re going to talk about non-small cell lung cancer. Thank you.