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John Leonard, MD (Host):  Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I’m your host Dr. John Leonard. And today we will be talking about head and neck cancers. My guest today is Dr. Doru Paul. Dr. Paul leads the Head and Neck Oncology Program at Weill Cornell Medicine and New York Presbyterian Hospital. He’s an expert in the treatment of head and neck cancers with a track record of developing successful multidisciplinary approaches to treat these complicated conditions. So, Doru, it’s great to have you here today. thank you for joining us. I think this is a very interesting and important topic for our audience. So, thanks for being here.

Doru Paul, MD, PhD (Guest):  Thank you very much for inviting me.

Host:  What led you to go into medical oncology and specifically head and neck cancer is a fairly specialized area. What led you get excited about working in this area.
 
Dr. Paul: Head and neck cancer, it’s an extremely interesting condition compared to other solid tumors. If you think of other solid tumors like pancreatic cancer or lung cancer; they tend to spread at a distance. Head and neck cancer has this peculiarity that it tends to return where it started. So you have local recurrence in head and neck cancer. And we don’t really know why. If you also think about the most common histology of head and neck cancer which is squamous cell, it very rarely goes to the brain compared to for example, lung cancer in the squamous cell histology almost 20% of the patients with advanced disease they ended up having brain mets. So, I consider head and neck cancer a very interesting disease and I think by studying it, we can also find out more and expand the knowledge that we’re obtaining from head and neck cancer to other locations.

Host:  So, head and neck cancer maybe you could tell us a little bit about kind of how common it is and how it typically presents itself. I mean my assumption is not being a specialist in this area, the head and neck are relatively small areas that are in some ways visible at least on the outside if not on the inside. So, my assumption would be that it tends to present itself at typically a fairly small stage because you would notice something before a tumor got very big. But is that correct or how does a typical patient present themselves?

Dr. Paul:  You are 100% right. Approximately I would say 40% of the head and neck cancers are presenting with an early disease and at stage one or stage two that are amenable to local treatment surgery and radiation. In contrast, to combine modalities, really recommended for the rest of the patients that are approximately 60% when they have advanced disease in stages three or four. There are also interesting factors and the United States, head and neck cancer is growing so the numbers of HPV positive patients in the United States have been growing since 1980 when this HPV positive disease was relatively rare until now when if you are looking at the numbers, the prevalence in oropharynx tumors in the 1980s was approximately 15 to 20% and now it’s approximately 70%. And this has been increasing due to the HPV virus to a rate of approximately 3% per year. And currently, approximately 18,000 of the oropharynx tumors are HPV positive. And it’s important to know this. Being HPV positive doesn’t necessarily mean that you are going to get cancer, this head and neck cancer. Less than 0.5% of HPV positive individuals develop oropharynx cancer.

In terms of the numbers of head and neck cancer, worldwide it’s a relatively common disease. There are more than 600,000 new cases per year. The United States in 2020 it is anticipated that we will have approximately 70,000 cases of head and neck cancer. This is mainly a disease of men with the majority of patients being men, approximately I would say something like 47,000 of men and then approximately 17,000 of women. And also, in terms of location, it’s also important to note that in the United States the majority of these cancers approximately 70% they are or oropharynx origin.

So, head and neck cancer is not a homogeneous disease. You have different locations and going from the top where you have the nasopharynx then going to the oral cavity in front and then oropharynx in the back and going down to the hypopharynx you have several conditions that are really treated differently. They have different origins. You have in the nasopharynx a disease that’s mostly related to the Epstein Barr virus and the disease is endemic in certain parts of the world like China. And then you go down in the oral cavity and the oropharynx, at the back of the mouth you have the tonsils and the base of the tongue and these are locations that are related to the HPV infection, the human papilloma virus infection mainly the type 16 and 18.

Going down in the hypopharynx, this is the location that is seen mostly in smokers but not only. This does not tend to be related to HPV. So, looking at head and neck regions, you need to really address each of it individually in terms of treatment and individualize the treatment in every patient.

Host:  So, first just to speak briefly about smoking. Any other risk factors and is there any screening that is recommended for patients or is it just dealing with things if symptoms emerge?

Dr. Paul:  So, first of all, smoking is the most important risk factor. Smoking one pack a day increases the risk of head and neck cancers by approximately 13 times. Besides smoking, it is also very important to note that alcohol consumption more than 50 grams per day is increasing the risk of six to seven times and of course also the combination of smoking and alcohol it’s increasing further the risk. There is a specific area in France called Calvados where people tend to drink a very hard liquor plus smoke and then they have a very high incidence of head and neck cancer. So, smoking and drinking liquor especially hard liquor is increasing the incidence of head and neck cancer.

Besides that, there are other factors that are important to note. Of course, the HPV virus, the incidence of head and neck cancer has a decrease in terms of age by a person ten years in males because of the change in sexual behavior in the United States. There are less common risk factors like for example, weakened immune system, patients that – and this is your area of expertise, patients that have Lymphoproliferative disorders, that are exposed to chemotherapies and their bone marrow is affected. They have an increased risk of head and neck cancer. Patients that have received bone marrow transplants, in general weakened immune system and then there are also certain dusts like for example silica dust or wood dust, some of the patients who have been working in certain industries that expose them to asbestos that can also increase their risk of head and neck cancer.

And not the least the cancer of the lipids related to UV light and some of these patients have been having burns, solar burns if you ask them. The head and neck cancer tends to be a disease of the elderly. With age, also the immune system declines, and you are seeing both increasing the head and neck cancer of the mucosa and of the skin, squamous head and neck cancers.

Host:  So, you alluded to a couple of viruses, EBV or Epstein Barr Virus as well as HPV. Just for our audience, how do these viruses, at a high level, how do they contribute or cause cancer formation in this particular setting?

Dr. Paul:  Yes so, these viruses are considered oncogenic viruses because they modify certain pathways in the cell. In particular, the HPV virus has this protein which is a P-16 protein which is elevated and the P-16 protein it’s enhancing the lesion of the cells and also the spread of the cancers cells to the lymph nodes. At the same time, there are also certain proteins inside the cell that are protecting the cell from damage like well known PP-53 gene that has this role of protecting the genome and the proteins of the virus, they are inhibiting the P-53 gene. There is a specific protein called the E-6 which is particularly oncogenic that is inhibiting the P-53 protein. There is another one called E-7 that’s inhibiting another protein that is protecting the cell, the original blastoma protein is inhibited by E-7.

So, they are modifying these transaction pathways and they’re making really the cells mortal and P-16 is also increasing the risk of metastases in the lymph nodes. This is why if you are looking at the patient with HPV positive disease, the presentation is different from the patients that are HPV negative and they are mainly smokers in terms of the lymph nodes. So, they tend to present with these large lymph nodes in the neck and not so large primary tumors on the mucosa. So, you can see the effect of this modified pathways and of the viral proteins in clinic.

Host:  So, before we move on more to treatment, I just wanted to get your thoughts on the HPV vaccination. It has obviously gotten a lot of attention in public health and obviously has a potential impact also in cervical cancer. Have we yet seen an effect on head and neck cancers, any aspect of it at this point or I would assume most of the effects will be with a longer latency period at some point in the future. Any thoughts around that?

Dr. Paul:  That’s a very, very important question. And this question is extremely important because on June 12^th, finally Gardasil 9 was also approved for prevention of head and neck cancers. So, it has been approved before for cervical cancer but for a week now FDA has approved the 9-valent issue vaccine for the prevention of certain HPV related head and neck cancers. A survey that was done by the CDC in 2016 showed that in 19 states, approximately half of the girls 50% of the girls and approximately a third of the boys, 37% of the boys were vaccinated. So, for the future, we expect really a decline in the number of the HPV related head and neck cancers. And again, approximately 18,000 of the head and neck cancers are related to HPV. So, the Gardasil-9 that is recommended now from age 11 to age 45 may prevent approximately 70% of the HPV associated head and neck cancers.

Host:  Oh, that’s good to know and I think an important take home point for our audience. And I know that many children have had experience with children saying I just got my cancer vaccine, in reference to the Gardasil. So many times, people want a cancer vaccine. This is one that actually fits the bill at least for certain things. So, how do we move forward in treatment? And my not being an expert in this area, my high level take on head and neck cancer is that it’s really a multidisciplinary approach and I know you’ve done a lot to set up a strong team here with your collaborators in surgery and radiation oncology. But tell us a little bit about the general approach to these cancers. What’s in common, what’s different based on specific situations and obviously, an important part of the care I’m sure our audience knows is the preservation of function whether it’s swallowing nutrition, voice et cetera.

Dr. Paul:  Yes you touched on some very, very important points. So, the first point is this multidisciplinary team. Compared to other locations, here you have a location that’s very visible. It’s really on the face and is modifying really the life of the patients because they may have trouble eating, they may have trouble swallowing, they may have trouble breathing. So, this is a disease that is treated really multidisciplinary and we have here at Cornell, an extraordinary team of surgeons that are really excellent and we have weekly tumor boards where the cases are presented by the surgeons that they diagnosed these diseases and then we have radiation oncologists that are also key in contributing to the local treatment. But compared to other cancer locations, you have also very importantly nutritionists that are here to help the patients and every single patient with head and neck are seen by a nutritionist to assess their nutritional needs.

We have also a support from social workers because some of the patients they need help with their transportation or some of them may need emotional support. And the key of success in treating this condition is communication, very good communication, a very strong team. We are literally communicating on a daily basis between us talking about patients, asking questions and we are very flexible when I have a patient and the patient needs to be seen by one of the surgeons. I just call them, and they will be seen in the next 24 or 48 hours. Same thing for radiation oncology.

So on the patients because of the side effects of the treatment, we are giving them radiation, they have severe mucositis, they may need also placement of feeding tubes. And this another specialist that needs to be involved with the radiology they need to be involved in the care by placing the feeding tubes and then you have speech therapy that’s also involved in order to reestablish the guttation so they are able again to swallow and we can remove the feeding tubes. And there is really this feeling among fields and if you are looking at the follow up for example of these patients, the follow up will be between surgery, radiation oncology, and medical oncology and we will see the patients in succession so they don’t have to see all three of us all the time but once the patient can come for a follow up with the surgeons, or they can come to the radiation oncology and then they can come to medical oncology.

In terms of the treatment, as you mentioned at the beginning, because this is in the localized stages of disease that is treated by surgery and radiation oncology. When there is more advanced in stages three and four, we have also a role the medical oncologists to add the chemotherapy to the radiation in order to sensitize the tumors to radiation. And in more advanced cases, we are giving the patient solely systemic treatments.

For head and neck cancer, it’s very important to know that this year, 2020, is the first year when for recurrent and advancement of metastatic disease, immunotherapy is the frontline of treatment. So, since 2008 until 2019 for more than a decade the extreme regimen that was developed by a team from Europe Dr. Vermorken from Amberg, Belgium was really the standard of care which was a combination of chemotherapy agents, very heavy loads, high doses of cisplatin and continuous infusion of five fluorouracil plus the Erbitux and now, after the Keynote to 48 study, pembrolizumab, which is a checkpoint inhibitor has been established as really the mainstream treatment for head and neck cancers, squamous cell in frontline either alone or in combination with chemotherapy. And the side effects that are seen with this approach are much less than the side effects that were seen with the extreme regimen.

So, this is really a very exciting time for head and neck treatment because now we have this checkpoint inhibitors that are used with much less side effects and with better results. Another interesting and important point is that if you are looking at other conditions and we are talking about stage four, you are talking about disease spreading at the distance in other organs, you are talking about stage four for example, stomach cancer, the disease has spread to the liver or lung cancer has spread to the bone. In head and neck, you have stage four when the disease has spread locally. So, when we are looking at the cure rates for this disease, for this condition, for head and neck squamous cell, you can achieve cure even in stage four. Of course, when the disease has spread to a distance like in the other patients like you have lung metastasis from the squamous cell of the head and neck, the prognosis is not as good. But in some of the cases, like the majority of the cases, the stage four is really related to local disease and it still can be cured in 20 to 30% of the cases.

So, when a patient hears I have a stage four head and neck, it’s important to ask the physician what type of stage four. Is it a local stage four that there are only some lymph nodes in the neck that are involved or is it a distal stage four where distal organs are involved. In terms of other areas of research, it is becoming apparent that some of the pathways that we mentioned briefly may be also targeted and this year at ASCOL, this year ASCOL was a virtual conference. There was a presentation that was looking specifically at a mutated gene called HRES and now there is an agent that can be specifically used for HRES mutated squamous cell tumors with excellent response even in heavily pretreated patients. So, obtaining information about the genes that are mutated through next generation sequencing methods is very important for these patients because this may lead to using agents that are well-tolerated that are oral and improve the survival of these patients with maintaining their wellbeing.

Host:  What percent of patients is that new target relevant for? And also what other areas of research are particularly exciting to you in this area?

Dr. Paul:  Approximately five to seven percent of the squamous are positive for mutations in the HRES. There are other mutations like the 63 C8 mutations, and we have Dr. Lewis Canby who has been really involved in this 63 C8 mutations and we have a study that’s is going to be open for this type of tumors. Approximately 30% to 40% of the tumors, they have this 63 C8 pathway mutation and they may benefit from agents directing the pathway. Besides this, we will open here a study that is looking at a combination of immunotherapies. We have the standard now which is the pembrolizumab the checkpoint inhibitor stimulating the immune system, so we designed here at Cornell, a study that is combining a local approach to stimulate the immune system by injecting an adenovirus directly in the tumor. The adenovirus has been modified to be expressed only in the tumor cells that have a high turnover, a high telomerase expression and it will kill specifically only those cells that express the telomerase. And at the same time, we are giving them the systemic treatment with a checkpoint inhibitor and also locally we are treating them with stereotactic radiation as BRT. So, it’s really a triple way to stimulate the immune system and hopefully this will lead to better responses and also improve the survival. So, this study is going to be open here really very, very soon.

Host:  Great. Well before we wrap up, are there any key messages you want to give to our audience and in particular, a message to patients and caregivers if they’re dealing with a diagnosis of head and neck cancer? Any key issues to keep in mind?

Dr. Paul:  Because of having this area which is really our way to communicate with the others, our face involved in the head and neck cancer; there is a lot of fear of this condition but the message that I would convey is that compared to other solid tumors, head and neck cancer is a curable disease and even if initially when you are treating this tumor, you may have side effects from the radiation or from chemotherapy. Better times are coming, and you can be cured.

Host:  Well thanks very much for a great summary of really the state of the art in head and neck cancer and key issues around why it’s so important to be treated at an institution or a center where there is great multidisciplinary care as well as cutting edge novel therapies in development. So, thank you for your great summary. I want to invite our audience to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at This email address is being protected from spambots. You need JavaScript enabled to view it. with questions, comments, and topics you’d like to see us cover more in depth in the future. That’s it for CancerCast, conversations about new developments in medicine, cancer care and research. I’m Dr. John Leonard. Thanks for tuning in.