Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And joining me today to give updated treatment options for skin cancer of the head and neck is Dr. Harishanker Jeyarajan. He's a head and neck surgeon in the Department of Otolaryngology. He's an Associate Professor at UAB Medicine. Dr. Jeyarajan, it's always a pleasure to have you join us. I'd like you to start by talking a little bit about the trends and demographics, the rates of skin cancer of the head and neck. What are you seeing in the trends?

Dr Harishanker Jeyarajan: Sure. No worries, Melanie. Thanks for having me on again. So, when we're talking about skin cancer in the head and neck, really what we're talking about is we classify skin cancer into non-melanomatous and melanomatous skin cancer. And non-melanomatous skin cancer primarily consists of squamous cell and basal cell carcinomas, among a few others as well.

We know that from a trend point of view, the incidence of non-melanomatous skin cancer is highest in the head and neck when you compare it to incidence over the rest of the body. So, we know up to about 85% of all non-melanomatous skin cancers occur in the head and neck, and over 50% of all cutaneous squamous cell carcinomas occur in the head and neck disease.

The head and neck is also one of the areas that has the most high-risk subunits. So, high-risk subunits are in and around the nose and the eyes, and in and around the ear. In those areas, the disease is much more likely to be invasive, so have a high-risk of invasive features such as invasion into the nerves, or into the associated lymphatics, and a much higher rate of nodal metastasis, with the rate being up to about 30% in some reported series, and accordingly has a much higher rate of disease recurrence and death.

Overall, when you look at incidence of skin cancer, particularly in non-melanomatous skin cancer, the distribution is a little bit disproportionate. So in the north, most skin cancers are relatively low, whereas in the south, so south of the Mason-Dixon, the incidence of skin cancer, particularly in the head and neck region, particularly of advanced head and neck disease, is much, much, much higher, probably akin to what we see in Australia. Now, Australia's incidence globally is about 1,100 people per 100,000 patient population, so south of the Mason-Dixon is very similar to that kind of incidence.

Melanie Cole, MS: So as we're talking about these predictors of high-risk lesions, demographics, where people live, speak a little bit about what you want primary care providers to be looking for, Dr. Jeyarajan, because they're usually going to be the first line of defense for a patient and what would send them to see a specialist in these types of cancers.

Dr Harishanker Jeyarajan: In general, most early skin cancers have a very good survival rate. And so most of them are picked up by a local practitioner, primary care practitioner, or a dermatologist, or a Mohs surgeon. So in general, we recommend anyone that has a high proclivity or tendency to develop skin cancers, which is, you know, non-melanomatous skin cancers have a direct relationship to UV light exposure. Both SCCs and basal carcinomas are both directly related to cumulative UV exposure over their lifetime. So once someone starts getting evidence of cumulative sun damage, so solar keratoses, wrinkling. And once they start getting these early lesions, they should be referred to a dermatologist or a Mohs surgeon to address them early and completely.

Now, the times when they should be referred to an ENT specialist, particularly in high-risk areas in and around the eye and the ear, if you're finding that you're having a recurrence, so if someone has a lesion resected but has an early recurrence, so within 6 to 12 months, then they should probably be referred to an ENT surgeon, because especially around the ear, it's very easy to geographically miss islands of tumor cells. And so, anyone with recurrent disease in and around those high-risk areas, particularly around the ear, you should consider referring to an ENT. For a Mohs surgeon, once you get to more than four stages to clear disease, particularly around the periauricular area, you should really consider referring to ENT. Because once you get to that stage, the risk of local recurrence is much higher, but also the risk of nodal metastasis significantly increases.

And then, when you get to lesion size, so if a tumor itself is larger than 2 centimeters, so if you measure just with a ruler, if the tumor is in one of these high-risk areas, let's say in the temple area, but is greater than 2 centimeters, you should really consider referral to an ENT surgeon or at least imaging the patient. Because you know that in these patients the risk of metastasis climbs from under 10% to at least 30%. You know that a tumor size greater than 2 centimeters has a significant association with disease-specific death. So, it increases the risk of death from this tumor itself by about 19 times. And it doubles the risk of recurrence. And so, any big tumor, particularly in the periauricular area, needs to be at least imaged for the possibility of nodal disease and referred to ENT. And anyone that has any clinical or radiologic evidence of metastasis already to the regional nodal basins should be referred to ENT because most of the nodal metastasis occur in the parotid gland, which is kind of really our domain.

Melanie Cole, MS: Thank you for such a comprehensive answer. And give us an overview of the various treatment modalities available today. What's exciting? What's changed? We're updating this podcast. Tell us what's exciting.

Dr Harishanker Jeyarajan: So from a point of view of management of early to intermediate stage non-melanomatous skin cancers, treatment really hasn't changed too much. The treatment paradigm is still surgery, plus or minus adjuvant or radiation therapy as required for early to intermediate stage disease, as well as immediate local reconstruction. And so, that's kind of stayed the same, and I think we do a pretty good job of managing that between us and the Mohs surgeons here at UAB.

When it comes to the management of intermediate to advanced stage disease, locally advanced stage, non-melanomatous skin cancers, and the management of tumors deemed inoperable, either due to local disease extent or due to patient comorbidities, that's when we started seeing some change that we kind of alluded to in our last podcast, and that's primarily with the use of immunotherapy, particularly Libtayo or cemiplimab following on from MD Anderson's data, early series work, as well as some of the work out of Australia, we know that for cutaneous SCCs in particular, we know that they tend to be much more responsive to cemiplimab, which is an immunotherapy agent. We assume this is due to the high mutational burden associated with UV light-associated squamous cell carcinomas.

And so, what this means is by using cemiplimab, we can get the body's own immune system to start to recognize the cancer cells and to fight the cancer cells. And because of that, we can use it either as an isolated treatment or as a combination with standard treatment protocols, which includes surgery and radiation therapy. And that's kind of what we're doing now. So, oftentimes what we're doing is for people that have intermediate to advanced stage disease that are resectable, but the resection could cause significant morbidity, such as having to drill out someone's ear, such as to resect someone's facial nerve, which would give them facial paralysis, or if there's a very significant chance that we will not be able to get clear margins because of the extent of the disease, particularly the proximity to the skull base.

What we will often do is we'll enroll these patients in a neoadjuvant treatment protocol where they will meet with Medical Oncology, and start on a series of doses of cemiplimab. Usually, we try and give at least two to three doses. And what this does is it primes the body's immune system to start fighting the cancer. Oftentimes, you can see an early effect, such as reduction in size of either the lymphatic metastasis or the primary tumor itself. And then, oftentimes, what we'll do is we'll plan to have the surgery after about three doses. And by doing this, we're able to then remove, hopefully, a smaller amount of disease, preserving function, attempt a more local kind of recon option to minimize posttreatment morbidity, and then assess for the tumor response in the specimens we send to the lab. And if you have a complete response, then we know that we've already done all the treatment we need to.

Now occasionally, if the disease is high risk, we'll add a lower dose of postoperative radiation as well, or we'll just continue with the immunotherapy for about a year. But this is kind of one of the promising areas because it's allowing us to treat patients with intermediate to advanced disease, but minimizing the treatment-related morbidity associated with the traditional surgical treatment paradigms. It's also allowing us to offer treatment to patients who present with inoperable disease, either because they're not fit to have a general anesthetic, or because the disease is so extensive that we're unable to get clear margins. And in these patients, again, sometimes we can use it to shrink the disease so that we can do the surgery, or we can just use it as its own treatment modality on its own. And so, this is something that's been developed at a number of different hospitals, but we at UAB are using it quite extensively to help offer innovative care to our head and neck skin cancer patients.

Melanie Cole, MS: Such an exciting time in your field, Dr. Jeyarajan, with the neoadjuvant therapies that you've just explained about. Now because this is quality-of-life-limiting, where these cancers are located, and you are a head and neck surgeon, and we've spoken about head and neck cancers in general before, you and I, and the intricate nature of when you do surgery on these. So, speak about the multidisciplinary role here because when you're talking about quality of life, then there's going to be reconstructive surgeons or plastic surgeons, dermatologists, there's so many people involved to help that patient get through to the next phase.

Dr Harishanker Jeyarajan: Here at UAB, we have for some time now had a dedicated Head and Neck Skin Cancer Tumor Board, that meets every Wednesday afternoon, and it is a multidisciplinary collaboration between ENT, Maxillofacial surgeons, and Surgical Oncology, Radiation Oncology, and Medical Oncology, as well as the Mohs Department. The Mohs Department often attends as well. We will often individually present our cases to the group to get everyone's opinion on what they feel is the best option for each patient moving forward.

As I said, we have our traditional paradigms that we stick to. But because as you said, treatment of any pathology in the head and neck has significant consequences to a patient's ability to communicate, to present themselves to the world, and to function at a social level. And so for that reason, while there are traditional paradigms that we do try to stick to, having such a multidisciplinary group allows us to think along different avenues and think laterally and come up with various different trials and treatment alternatives for patients in order to make sure that they maintain good quality of life, as good as possible, and still get a durable response to their treatment.

From the point of view of head and neck reconstruction, that is a key part to this process. Most of the reconstruction is often performed by the ENT department. So, it's either myself, Dr. Chris Thomas, or Dr. Andrew Fuson. And this includes both static reconstruction of cutaneous defects, but also facial reanimation in the situations where the facial nerve has to be sacrificed either partially or completely.

Melanie Cole, MS: Wrap it up for us. This is a really interesting and timely topic. So, please wrap it up with your best advice, Dr. Jeyarajan, for other providers. You're always such a great guest, so informative, and you give us such great insights into these intricate cancers. So, please give us your best summary here.

Dr Harishanker Jeyarajan: So, head and neck cutaneous malignancies, particularly non-melanomatous in the skin cancers, are increasingly common in the south of the U.S. at rates comparable to Australia, which has the highest national rate globally. And this is due to significant lack of understanding of sun care, the use of sunscreen, the wearing of hats, long-sleeved clothes in the sunshine.

It's really, really important that we educate our young to try and do this to prevent cumulative exposure, which is directly related to the incidence of squamous cell cancer and basal cell cancer in the head neck region. Once you do start showing signs, it's really important that these patients are referred to a dermatologist for ongoing skin surveillance, and in patients that have recurrent disease, particularly in the high-risk areas, such as in and around the eyes and in and around the ears, in patients who have recurrent disease or clinical or radiological evidence of either lymphatic metastasis, which is usually the parotid, or signs of nerve dysfunction such as numbness in the face or weakness in the muscles or facial expression, they should be immediately referred to the ENT department here for further workup and consideration of clinical trials using neoadjuvant immunotherapy or definitive immunotherapy, as well as other surgical options, both ablative and reconstructive.

Melanie Cole, MS: Thank you so much, Dr. Jeyarajan, for joining us and giving us such an eye-opening interview. Thank you again. And for more information, please visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.