Overview of Cutaneous Squamous Cell Carcinoma

Overview of Cutaneous Squamous Cell Carcinoma Management

 Let’s talk about immunotherapy. Immunotherapy is a new paradigm in oncology. Before we used chemotherapy, which pretty much destroys all the cells that it gets ahold of, so it’s not very efficient, but it covers a wide area. You can also use targeted therapies, which target either certain cells or certain tissues. That has not been approved yet for squamous cell carcinoma. But what we’ve seen lately is the rise of immunotherapy.

Now what immunotherapy does is it helps the body uncloak tumors. If you think of it this way, as the body trains itself, as it trains its immune system to protect itself from tumors, it also trains itself to protect itself from attacking its own cells. It’s called protection against self-immunity, going after one cell. There are receptors that are on the surface of the cells, tumor cells and also normal cells, that tell the T-cells in your body, which can attack tumors, to leave them alone. So it can help protect normal cells, and tumors have evolved ways of exhibiting these receptors on their surface as well so they can also tell the T-cells to leave them alone.

And what immunotherapy does is it blocks the interactions between the receptors on the tumors and the receptors on the T-cells. So the T-cells now no longer see that tumor as cloaked, which it uncloaks the tumor, and now the T-cells attack the tumor. That’s basically what’s going on with immunotherapy in a nutshell. Those interactions can occur in different places. They can occur in the tumor bed itself, what we call the tumor microenvironment. They can also occur in the lymph nodes, and in other places: almost every cell in the body exhibits to some extent these receptors.

Around about 2013, 2014 or 2015, we saw a rise in immunotherapeutic medications for different cancers. Some of them are being used for the head and neck communities, squamous cell carcinomas of the head and neck. Pembrolizumab, nivolumab and also cetuximab are different immunotherapies that have been used for head and neck squamous cell carcinoma. But in the past few years more and more research has been done with a medication called cemiplimab. Now cemiplimab is what we call a PD-1 [programmed cell death protein 1] inhibitor. I mentioned those receptors. There are PD-1 receptors on the surface of T-cells and PD-L1 [programmed death-ligand 1] receptors on the surface of tumor cells. And so if you block the interactions, the T-cells will attack the tumor cells more efficiently.

The most recent agent that was approved was cemiplimab, and that drug was approved in 2018. Toward the end of 2018 that drug was approved for use in advanced squamous cell carcinoma, and what we mean by advanced is the disease is locally advanced or metastatic. And the types of patients that the medication is used for are patients with locally advanced or metastatic squamous cell carcinoma. They’re not candidates for curative surgery or curative radiation.

How is immunotherapy different from chemotherapy? I would say it’s more of an efficiency. Chemotherapy is more targeted therapy. It uncloaks the tumor cells, and the tumor cells that have more inflammation—like squamous cell carcinomas, they tend to have more inflammatory cells within them&mdash;are better targets for immunotherapy.

Now immunotherapy does not destroy all cells in the nature that chemotherapy will. But it can have adverse effects on almost every organ system in the body because you are waking up the immune system not only in the tumor but also in any organ system. So unlike chemotherapy, you don’t lose your hair with immunotherapy, but you can still have effects on your lungs, your kidneys, your colon or your skin. Those are the main side effects that we see. It can also affect your endocrine system, which is your thyroid gland, and other glands can be affected as well. Pretty much almost any systems can be affected by the drug as far as adverse effect goes. But luckily the adverse effects that we’re seeing with the newer immunotherapy agents are lower than we’ve seen in some of the older agents, and certainly in a general sense lower than in chemotherapy. I would say the best way to describe them is they’re more efficient. You have better outcome with fewer adverse effects.

How do we manage our patients’ expectations with immunotherapy? It really depends a lot on what type of tumor they have. But what we can tell patients in a general sense in comparing that to chemotherapy is that we can expect better outcomes. The studies show that immunotherapy has a higher likelihood of attaining a response, either a partial or complete response, than most chemotherapies. We can also describe clearly the adverse effects and more how to manage them.

Patients can sometimes start to see tumor shrinkage with the first or even the second dose of immunotherapy. With cemiplimab, the agent that’s approved by the FDA [Food and Drug Administration] now for treatment of locally advanced or metastatic squamous cell carcinoma, you can see response as soon as two months, and sometimes it can take four or five months, depending on the tumor. The metastatic tumors actually respond more quickly than the locally advanced tumors. For whatever reason that seems to be the case so far.

Oftentimes within the first few months patients can start seeing benefit. After the first two or three doses they also may start seeing some of the adverse effects as well, and depending on how severe they are, that would help us guide how to manage those as well. Do we need to stop the drug and give them a break from that? Can we continue with the drug and just manage the side effects? Or do we need to stop the drug completely and not restart it? It really depends on how severe the adverse effects are and whether we can get them back under control easily.

How do we decide when a patient’s eligible for immunotherapy? What we’re looking for is to determine if a patient is a candidate for curative surgery or curative radiation. That decision usually takes place in what’s called a multidisciplinary team where several physicians are involved. Maybe an oncologist, maybe a Mohs surgeon, maybe a radiation oncologist, maybe a head and neck surgeon, and maybe a patient advocate or someone who can explain to the patient in even more detail or be on their side as far as navigating care for the patient is oftentimes involved and on the team as well.

Cutaneous Squamous Cell Carcinoma: What Is Immunotherapy?

 For cemiplimab, the dosing schedule is actually quite simple. It’s given as a 30-minute infusion every three weeks. There’s really only one dose that you can give. It’s an IV [intravenous] infusion. It doesn’t take very long to deliver the medication to the patient. It’s a full vial of medication that’s delivered in either a 100 milliliter IV bag or maybe 500 milliliter, depending on how the doctor chooses to infuse it. The patient generally doesn’t feel much during the infusion. They sometimes may feel something, maybe that it feels a little different. But most of the time the adverse effects, if they were going to occur, don’t occur until the second, third or fourth infusion that they have.

So as far as the patients go, it’s not a huge barrier. They do have to go into an infusion center to have the infusions done, or an oncologist or a dermatologist’s office that does infusions. That’s one thing, they have to come in and be monitored while they’re there, to be carefully watched to make sure they don’t have immune-related adverse effects that could occur. During the infusions, it’s possible that the immune system can wake up even during the infusion and they can have a adverse effect that occurs more immediately, but it’s more likely that it would occur later. As far as that being a barrier, coming for the IV, it’s a short infusion so it’s not a huge barrier to a patient. That’s nice to see.

What’s the response with cemiplimab? The study showed that the response rate is about 50%. If you look at all the people who responded partially and all the people who responded all the way or had complete responses, that’s about half. So I tell people that about half of the time you’ll see a response, and that’s a good thing. It’s actually much better than some of the older therapies that we had, in which that percentage would be in the 20s or 30s. So actually, it is a better therapy as far as that goes, and that’s why it’s sort of risen to being recommended first-line as a treatment for locally advanced in a metastatic squamous cell carcinoma.

How do the data that we’re seeing in the real world compare to clinical trials? I think it would be very similar. I think the trials have continued to show benefit over time, the real-world outcomes have been very similar. There haven’t been really any more data published on that since some data were released last summer in a major oncology meeting. We don’t really have more long-term real-world data. In my own experience, the patients have done just as well as they have in the trials as far as the outcomes, and in a general sense it’s very similar. It’s nice to see that the real-world data in just my personal experience match the trial data.

As far as adverse effects go, the serious adverse effect rate is actually pretty low. We talked about more serious adverse effects being maybe in the 1% to 5% range of patients. Most people who have adverse effects are mild-moderate, and they’re typically easily managed with simple treatments like systemic cortisone, prednisone, sometimes even a topical steroid, or sometimes management by an endocrinologist for their thyroid, which can be made abnormal by the treatment.

However, an abnormal thyroid test is not necessarily a reason to stop the medication because that can be managed. With other side effects such as diarrhea, or if they have autoimmune pneumonitis, that has to be addressed. They all have to be addressed seriously. But for severe side effects involving the lungs, the kidneys, or the GI tract, the gastrointestinal system, if they’re very severe the patient can’t take that medicine any more. But for thyroid, they continue to take their medication in some cases, even though their thyroid abnormalities are being managed. So some side effects you can treat through, and other side effects, you can’t.

Experience With Immunotherapy in cSCC

The multidisciplinary team is important, and that really should be employed any time major decisions are being made as far as major inflection points in a patient’s care, when you’re making a big decision about what you’re going to do for a patient. The team players are typically dermatology, medical oncology, radiation oncology, and head and neck surgery. General surgery sometimes is involved as well. And then oftentimes, a patient advocate may be involved as well. And then of course the center of that is the patient. The patient’s in the middle of the multidisciplinary team because they’re the person who’s being affected by all of this.

That is the typical team. That may vary from site to site. For example, in the community you may not have access to all of these different players. In the academic center, typically the multidisciplinary team has already formed, and it might meet on a regular schedule so patients’ cases can be discussed. It’s important that for community physicians, and for patients, to be aware that even a community physician can create a multidisciplinary team by having those players in their back pocket so they can discuss cases with them, which is very important.

It’s very important not to make decisions, big decisions, for patients by yourself because there may be other options that may not be considered; not that the physician wouldn’t know all the things, because I’m sure they’re very up to date on care if they are using this kind of medicine. But all the options should be presented to the patients so they can make an informed decision.

That’s important to be able to reach out to a radiation oncologist, or to your head and neck surgeon. Call your oncologist and talk about the patient, or maybe call another member of the team, maybe a Mohs surgeon. If you’re a dermatologist or if you’re an oncologist, you may call a Mohs surgeon and talk about the surgical options. And again, there are also combinations. And so combination therapy, or what we call adjuvant therapy, has not been studied in squamous cell carcinoma very well yet. It’s just a little bit of information coming out, but that’s when you combine different therapies, and that’s more what physicians may do when they know all the different pieces of data. They can decide if more than one therapy might be useful for a patient, used in combinations together. But unfortunately, there’s no FDA [Food and Drug Administration] approval for what we call adjuvant therapy when it comes to immunotherapy for squamous cell carcinoma.

What’s the patient’s role? Well the patient’s role is everything. They are the ones affected. The patient’s role is to receive the information from the different physicians that they have and ask questions and understand the care that they’re receiving. If they need help, they ask a family member or a patient advocate or do their homework and research to make sure that they’re getting what they’re looking for. But the patients’ role is to seek the highest quality care they can and to make sure that they’re getting the best out of the health care system to help them be cured, if that’s possible.

In advanced disease, how does the health care professional determine if a patient receives palliative care or if they’re going to have medication? I think that’s a joint decision between the health care provider and the patient. I think every patient sits in their own space in the health care system, and within their body and within their disease state. I think as far as palliative care, generally there are guidelines for palliative care as to a patient if they choose not to have further therapy, or maybe the determination might be made between the patient and physician that their life expectancy is not longer than six months, or whatever that guideline might be. But I think that’s one of those decisions that unfortunately can’t be answered just in a general sense. It’s going to be a decision made between the patient and their health care team.

How are treatments evolving? It’s pretty incredible actually. In our space in oncology/dermatology, the rate of advancement in pharmacology is incredible. There are so many new therapies that are coming down in the market. There is a tremendous amount of research being done by multiple companies. We’ve gotten better and better at understanding the immune system and finding targets that are either receptors on tumors or certain types of cells or things like that, and being able to tune the immune system to fight cancer in a more efficient way.

I think that patients have to look forward to a lot of innovation in dermatology and oncology and surgery and drugs in the general sense. So I think for patients, rest assured, there’s a lot of innovation going on, and they will benefit from that. We will all benefit in that over time. It’s a great time for us to be learning in our space.

Decision-Making Surrounding the Treatment of cSCC

® program: “Considering Immunotherapy for Cutaneous Squamous Cell Carcinoma.” I’m Dr. Anna Pavlick, the director of the Melanoma Research Program at NYU Langone Perlmutter Cancer Center in New York. Joining me for this discussion is Dr. Anthony Rossi, a dermatologic surgeon at Memorial Sloan Kettering Cancer Center in New York.

Today we are going to discuss immunotherapy, a novel treatment strategy that uses the body’s immune system to fight cancer. Specifically, we’ll be discussing how immunotherapy is being used to treat cutaneous squamous cell carcinoma: the second most common form of skin cancer.

The first topic we’re going to talk about is an overview of the squamous cell carcinoma of the skin. Dr. Rossi, how would you explain cutaneous squamous cell carcinoma [cSCC] to patients in the context of skin cancer?

Hi, Dr. Pavlick. Thanks for having me. When I try to explain squamous cell carcinoma of the skin, I want to have the patient understand what type of skin cancer it is. We actually started to call squamous cell carcinoma keratinocyte carcinoma, to differentiate that from the old terminology, which was nonmelanoma skin cancer.

Squamous cell carcinoma is the second most common type of skin cancer of the skin, and it usually is associated in category with basal cell carcinoma, which is another type of keratinocyte carcinoma. We try to make this distinction because these 2 types of skin cancers come from epidermal or skin cells or the skin keratinocytes, and that differentiates it from other types of nonmelanoma skin cancer like Merkel cell carcinoma or adnexal carcinoma. So we like to make that distinction right off the bat.

Squamous cell now represents the second most common type of skin cancer: the first type is basal cell, the second type is cutaneous squamous cell carcinoma, and the third type is melanoma. We even go on further to make a distinction between squamous cell carcinoma that’s arising from the skin, the skin of the head and neck, or the skin of the body versus squamous cell carcinomas that arise from the mucosal surfaces like the inside of the mouth or the genital area because those also behave differently.

Are there any factors that put patients at risk for developing cutaneous squamous cell carcinoma?

Sure. We know that squamous cell carcinoma of the skin is actually increasing in incidence. It’s actually increasing every year, and we know there are certain factors that predispose patients to getting this type of skin cancer. The No. 1 factor is UV [ultraviolet] radiation or exposure to the sun, so either artificial tanning or natural sunlight tanning is a risk factor because those with fair skin and light eyes and white hair are at already predisposed to getting this type of skin cancer. Though it’s the second most common type of skin cancer, there are about a million cases per year in the United States of squamous cell carcinoma of the cutaneous origin. That was in about 2018, and we know that most squamous cells do pretty well, but there will be a subset that either metastasize to the lymph nodes or have regional metastasis or even distant metastasis, so it does put the patient at risk for disease death or death due to disease.

Another factor that we know contributes to the risk of developing cutaneous squamous cell carcinoma besides UV radiation is immunosuppression. Whether they are immunosuppressed because of genetic reasons or from medications they’re taking to suppress their disease, or other immunosuppression from HIV/AIDS, or organ transplants, these patients are at higher risk we know for getting squamous cell carcinoma of the skin.

Again, if it’s not an underlying genetic thing, is there really anything that patients can do if they don’t have something intrinsic to really help reduce this risk?

Definitely. We always advocate for our patients to use good sun protection and to not do artificial tanning or even natural sunlight tanning. Tanning just once actually increases your risk of getting not only a cutaneous squamous cell carcinoma but also melanoma, as we know. Just using really good sun protection—daily sunscreen with SPF 30 or above&mdash;is very helpful. Also, regular measures like wearing some protective clothing&mdash;hats, sunglasses, sun shirts&mdash;is really helpful if you’re going to be outside exercising or at the beach. It’s important to understand that there is no good way to get a tan and always use protection when you’re outdoors.

Great. I know it really has a lot to do with the rise of skin cancer that we’re seeing now. And I know also there have been a lot of campaigns trying to increase awareness. But we really need to make an impact on our young people and the children to start being much more aware, so that as they grow into adults, we’ll be able to see a decrease. I don’t know about you, but growing up we were always outside playing, we were always at the beach, and I don’t recall ever having sunscreen on because it just wasn’t something that was done. But now I see a lot more parents always putting sunscreen on their children, which makes me really happy.

Definitely. Even for myself, growing up, I never wanted to put on sunscreen, but now I put it on religiously. It’s really helpful that we’re getting the campaigns out to the younger population, because really preventing these burns or this exposure earlier on can help prevent developing these skin cancers later on.

CSCC in the Context of Skin Cancers and Risk Factors

For many of the skin cancers that you and I deal with, it really takes a village to take care of the disease. In your perspective, who do you think is really integral in dealing with the management of these carcinomas?

That’s a great point. Not all squamous cell carcinomas are created equally, so we like to say there’s a low-risk squamous cell carcinoma and a high-risk squamous cell carcinoma. We try to make that distinction because it helps us divide the management of this. Patients who are at risk for getting these types of skin cancers—the fair-skinned individuals or the patients with a history of tanning or excessive burns or even a family history&mdash;should be screened by their dermatologist at least once a year to make sure there are no changing lesions or any changing moles that can predispose them to other skin cancers. We really do like to get them in a regular routine screening pattern. Of course, if they’re going to their regular general practitioner and they see something on one of those exams, then they can be referred appropriately. But it’s also important for the patient just to check their own skin, especially if they’re noticing that there’s a pink spot that’s scaling, that could be the sign of an early precursor lesion that can develop later on into a squamous cell. Those are called actinic keratosis. Those usually start out as these red scaling patches or little spots that happen frequently on the head and neck and in sun-exposed areas.

If that is the case, then going to see your dermatologist is helpful because there are many ways that we can stop those precancers and treat them before they turn into squamous cell carcinomas.

 Clearly we know that the earlier you catch something, the better the outcome. I would assume that that’s exactly how you feel. If we can get patients to see dermatologists on a regular basis, even patients who may be seeing an oncologist, just to raise awareness that skin lesions are easily manageable when they’re early stage and that this is something that you are critical in helping us to manage.

Many of the therapies that patients are given as oncology patients can sometimes predispose them to early stage skin cancers as well, and I think it’s helpful to have a really united team that works for the patient’s best interest in preventing these things from happening.

We do get a lot of referrals from our oncology colleagues because many of those patients are at higher risk for getting a skin cancer because of the immunosuppressive medications that they’re on. We like to say that if they’re caught early, you can actually cure early low-risk squamous cell carcinomas mainly by just cutting them out. The surgical option is very good for these early stage disease and early stage lesions, and that’s really helpful because we can prevent those from spreading if caught early and if managed appropriately with regular surgical excisions.

OK. And can you talk a little about the type of excision that gets done for these lesions?

For low-risk skin cancers, especially squamous cell carcinoma, we think of the low-risk body types as the arms, the trunk, the torso. These are areas where we can readily excise them just doing a wide local excision for invasive squamous cell carcinoma. If it’s even more superficial and it’s just in situ, meaning just in the top layer of the skin, then we can do some other curative procedures such as scrape and burn or electrodesiccation and curettage. There are also topical chemotherapies that can be used off-label for these types of early lesions or in situ lesions. So we have multiple ways we can treat these in situ lesions early on to prevent them from growing or spreading further.

CSCC Diagnosis and Early Stage Definition

Moving on to our next topic, which is the surgical management of advanced-stage metastatic squamous cell carcinoma of the skin; how would you define the difference between advanced versus metastatic cutaneous squamous cell skin cancer?

The high-risk skin cancers, squamous cell carcinoma, are those that are mainly occurring on the head and the neck, especially the mask area of the face. If you had put a mask on a head, you would notice that around the eyes, the mouth, the ears are higher-risk areas that predispose these patients to getting more aggressive lesions in this area. So we really take into account where the squamous cell carcinoma is developing. If the histology is poorly differentiated, if it’s not well differentiated, we know that those can be more aggressive. They can invade; they can spread.

If recurrent tumor has already treated and now has come back, that’s at a higher risk for spreading. In these areas, when we think about these T1 lesions, as we’d call them, those are still amenable to something like Mohs surgery if it’s occurring on the head and in the neck and you use a precise, complete circumferential margin control with histology to really guide the surgery and to make sure that the roots of the skin cancer have been excised.

When those skin cancers have progressed even further and now have developed either in-transit metastasis or regional disease including the lymph nodes, those become an advanced presentation. Now we really need a multidisciplinary approach with our oncologists and our radiation oncologists. We’d like to stratify those lesions as being at higher risk of course, and we need a multidisciplinary approach to treatment.

 I think it’s so important, especially once these patients get referred to either the head and neck surgeons, that radiation and medical oncology in conjunction with dermatology really discuss this with the patient and what should be done. Because with the onset of these new therapies, like immunotherapy, many of these lesions can be treated without patients having a very disfiguring or aggressive surgery. Now is the big buzzword is neoadjuvant therapy. So using systemic therapy prior to a surgical resection essentially to make the surgery less invasive or less aggressive is really something that really needs to be a multidisciplinary discussion.

Yeah, I agree. I think now is an exciting time because we have even more options to treat these patients without having them undergo a very morbid surgery resection or even possible radiation at some point.

If you get a patient who has an advanced or a metastatic squamous cell, are there any specific tests you’d like to order to work up their metastatic chances?

Surely. We know in the high-risk squamous carcinomas, in-transit region node metastases are the most common. Of course there’s the risk of distant metastasis as well. So there are some variables that are associated with a higher rate of metastasis. If a tumor diameter is greater than 5 centimeters, if it’s poorly differentiated or if the tumor thickness is greater than 6 centimeters and invading into the subcutaneous fat, these all have higher associated risk of local or regional metastases.

The sentinel lymph node is still a bit controversial in squamous cell carcinoma, depending on where you practice or which hospital system you’re in, but I think it’s important to get imaging and an imaging work-up if you’re presented with one of these higher-risk squamous cell carcinomas. Of course your physical exam is important, just to make sure there’s palpable lymphadenopathy in the region, always doing a very thorough physical exam to make sure. Getting baseline imaging can be very helpful, especially if the patient is also complaining of certain neuropathic pain, such as tingling or burning in that area. That could be a tip-off that there is something called perineural invasion or the tumors wrapping around a nerve.

Advanced Versus Metastatic CSCC

How do you decide between surgery and radiation if a lesion is just too large for a dermatologist to manage?

That’s a great question. I think we now have better staging criteria for squamous cell carcinoma. We used to rely solely on the AJCC [American Joint Committee of Cancer] staging criteria, but recently there is the Brigham and Women’s staging criteria, which has really helped delineate which ones are at higher risk for these local recurrences or local and regional metastasis.

This Brigham and Women’s staging has T1, T2a, T2b and T3. The T2b and T3 are the ones that are associated more with these higher events—as you would say, the metastatic spread. T2b and T3 have either 2 or 3 risk factors, or the T3 class has four risk factors or bone invasion. And the risk factors that they determined were tumor greater than 2 centimeters in diameter, poorly differentiated if there is perineural invasion on histology, either on the biopsy or the final excision, or if there’s invasion beyond subcutaneous fat.

Hopefully, the original biopsy would get these criteria if the biopsy encompasses a big part of the lesion. But sometimes we don’t know all these factors until either we’re doing the Mohs surgery at that time or we get the pathology back after a wide local excision if a different modality was used. In that case, when you do have complete histology and you can identify these risk factors, it’s time to determine whether you would proceed with adjuvant radiation or adjuvant immunotherapy if needed.

I’m currently running a clinical trial looking to address whether patients with those high-risk factors, because it’s common that they would go on and have adjuvant radiation, will benefit also by getting adjuvant immunotherapy following radiation? I think it’s a very important question because we know that radiation is very effective in controlling localized disease but does very little to prevent systemic diffused disease.

This clinical trial is asking the question, “Can we minimize the chances of local recurrence by giving standard-of-care radiation?” Half of those patients will go on to observation and the other half will go on to receive a year of adjuvant immunotherapy. That’s going to be a very interesting trial, to see if that can then impact the survival of these patients.

That’s really exciting. That’s a superimportant question that we need to know because while, as you said, adjuvant radiation is associated with good disease control after an excision that either has very close margins or positive margins, we don’t know how well it’s doing for the distant disease.

CSCC Staging Criteria: Surgery or Systemic Therapy  

When you look at a patient who’s got locally advanced disease—I think we’ll take metastatic disease out of the picture right now&mdash;let’s say multifocal lesions on the scalp or even some local lymph node disease, I’m essentially thinking about these head and neck carcinomas that are really pretty common. At least they are for me. Is there any variable that would sway you to not want to give people immunotherapy and think about if we should do surgery instead, or talk about radiation rather than immunotherapy for this local control, because it’s just too diffused for you to manage it surgically?

 Now we are having even better discussions with the patient, mainly the shared decision-making, as we like to call it. Really engaging the patient to see what their wishes are. Surgery is feasible in many cases, however, it’s not without its morbidity, especially when these tumors are close to the eyelid, close to major structures like the nose. If you proceed with surgery, while you may be able to achieve negative margins, you may be actually removing critical structures. That has a lot of quality-of-life issues down the road and even just morbidity for the patient.

If we have good preoperative staging and we know that these tumors are deeply invasive, then we know there’s an increased risk of local recurrence or even regional metastasis to the lymph nodes. At that point it’s really crucial to present the patient with all these options, including immunotherapy, because if they do have a good response to immunotherapy, they may be able to forgo the radical resection.

I agree, and I’ve recently come across a couple of patients, because I think it’s very important that patients truly understand the potential benefit of immunotherapy. Not all patients are going to respond to immunotherapy—only about 50% will. But we also have to thoroughly go through the potential side effects, because even though they are small, some of them may be lifelong, such as the endocrinopathies.

When you deal with older patients, some of them are more willing to accept more risk with respect to immunotherapy toxicity because they don’t want surgery. But I’ve seen a lot of younger people say, “I really don’t want to take the chance of being subjected to insulin-requiring diabetes,” even though it’s a very, very small risk. It is a risk, and they would opt more to have a surgical excision than be subjected to the risk of a lifelong medical issue.

Agreed. Age is an important factor, though we are seeing squamous cells now even presenting in younger patients. Granted, those are usually very early, which are curable with regular surgery. But even in our middle-aged patients or patients who are maybe considered older but still have an active lifestyle, a large resection of the entire scalp with lymph node removals, that can predispose them to a lot of morbidity later on. These are all important questions that we need to ask, not only the patient but ourselves, to see what the best initial treatment might be in these larger, more complex locally advanced disease.

 That really is the take-home message: this is not a unilateral physician decision. It’s not really a group of physicians making that decision. Yes, we can give our recommendations, but as health care providers really need to incorporate the patient into that decision-making process, because even though my inclination might be, “Yes, I really think you should do immunotherapy,” I’ve had some patients say, “I think I’d really opt for radiation therapy.” Many times they do have a valid reason, and many times they don’t. But it really is such a multilevel discussion about the right option because there is no right answer.

Agreed. Just knowing their home situation is important for all these treatments. How they’re going to get back and forth to the hospital or how they’re going to get to someone’s office. These are all smaller points, but they really build up a bigger picture.

Locally Advanced Disease: I/O or Surgery Decision Factors

When we talk about immunotherapy, a lot of times patients will always say to me, “What exactly are you talking about? Are you going to take cells from my body and give them back to me?” So how do you frame it for your patients to explain the mechanism for how anti-PD1 [programmed death-1] therapy in squamous cell carcinoma works?

It’s an interesting concept that they’re not always ready to fully understand, but it’s something that piques their interest. I tell them there is a reason why immunotherapy has been tried for a squamous cell carcinoma because it’s a type of skin cancer that has a high mutation burden. There are many mutations found in these cutaneous squamous cell carcinomas, and because of that we can harness the power of the immune system to try to recognize it as foreign and then attack it.

Mainly the squamous cell carcinoma acts through this PD-1 pathway to actually evade the immune system and to hide from it, but by using these types of immunotherapies, these PD-1 inhibitors, we can stop that evasion and get the immune system to hopefully recognize that skin cancer and destroy it.

Yeah, especially now in the COVID-19 [coronavirus disease 2019] age, where everybody is home watching TV, I think every patient has seen 

, where the squamous cell cancer is the alien ship, and it’s got its protective force field around it, and our T cells are really those fighter jets trying to attack it. Until we give them PD-1 and figure out how to break through that force field, I liken the PD-1 to putting holes in the force field, so our T cells can get through and kill that mother ship. Everybody says, “Wow, that really makes a whole lot of sense,” because everybody has seen that movie. That’s something I like to share with my patients because it helps them better understand the mechanism on a more simplistic manner, so they can go home and share that with their families.

In treating patients with anti-PD-1 therapy, namely cemiplimab, based on an every-three-week schedule, do you have issues with your patients keeping on that track, staying on schedule because of toxicity? When do you start to look for response, and when would you say, “Yeah, I don’t think this is helping.” When do you expect to see a clinical response once you start immunotherapy?”

I would actually put this question back to you. I usually partner with my medical oncologist, so we work in tandem. The medical oncologist is prescribing the medication, and we’re also seeing the patient in tandem—not to overburden them with visits but to make sure that we’re seeing a clinical response and that we’re not seeing anything new pop up in the area as well, like any new skin lesions. But we rely on our medical oncologists to help us with this. We can definitely provide a more clinical response to see how the tumor is shrinking, but I would ask you that question: how do you see them?

Yeah, we tried to do the same, working in conjunction with my dermatologist, who also becomes very helpful to me as well if the patients were to get any cemiplimab-induced rashes, so everybody is on the same page. I think patients do exceedingly well and don’t deal with a whole lot of toxicity, so they’re not immunocompromised. They don’t really feel that fatigued. They’re not dealing with the same cytopenias that we see with chemotherapy. Clearly for me, the biggest complaint of most patients is really itching and rash, and that is not usually a reason to hold a patient’s next therapy. You can usually manage it in the interim, get it under control, and keep people on schedule.

How many cycles? That’s really an individual question, because I’ve seen some patients have a very dramatic response after one cycle. I know it’s working, so I feel confident that we’re moving down the right path. However, there are some patients for whom I’m just not really sure, so I’m very compulsive about taking measurements of the lesions every time the patient is in the office with photographs. Clearly if the patient has not had any response within three to four cycles, I’m calling it a day. If I see the lesion growing, I’m going to raise the flag a lot sooner and say, “I don’t think you’re benefiting from this therapy.”

I think that’s superimportant because it is an evolving decision. As the patient is being treated, we’re always looking for response. If we’re not seeing that, then we need to move on to something such as a surgical or radiation intervention. Then we have that time to do that, and we’re acting quickly enough.

Yeah, that’s so important: not to lose that window of opportunity to move on to something else.

We often get called as well, as you were saying, for evaluation of any rashes that happened while on immunotherapy. We really try to be cognizant of how the patient is doing as well, especially if they’re getting an advantage from the immunotherapy and they’re responding. If the patient is comfortable enough, sometimes we can treat through these rashes with either topical corticosteroids and/or antihistamines. Sometimes we do actually have to give oral steroids as well. I was wondering how you feel about that. Do you think it dampens the response, or do you try to avoid oral steroids in these patients?

It depends on the degree of the rash. I always try the topical hydrocortisone creams, oral antihistamines, Pepcid, Benadryl, Claritin. When people start telling me that they can’t sleep because they’re up all night itching, that’s when I decide it’s time to give them a short course of steroids, oral corticosteroids. Sometimes a Medrol dose pack or just a short course of the six days will be sufficient. Depending on what that rash is being coupled with, where the itch is being coupled with a diffuse rash, I may opt for a two-week prednisone taper, a little bit of a higher dose followed by a decrease every three to four days. By the time they come back for their next cycle, they’re off all corticosteroids.

Anti-PD1 Therapy and CSCC

If we are presented with a very aggressive squamous cell carcinoma, we do talk to their transplant team or their oncologist to see if we can lower the immunosuppression if they’re on certain types of like calcineurin inhibitors for the solid organ transplant patients. But is there a role for immunotherapy in these organ transplant patients or CLL [chronic lymphoblastic leukemia] patients?

The jury is out. For the organ transplant patients, if we look at the melanoma population that has gotten metastatic melanoma, we try to lower their immunosuppressive agents. In the limited amount of literature out there, most patients who get anti-PD-1 inhibitors do have organ rejection, so it really is what organ have they had transplanted.

If you’ve got a patient who has had a kidney transplant but has diffuse metastatic disease, have a heart-to-heart conversation with the patient, saying, “We might be able to turn this metastatic disease around if we give you these immunotherapies. But you need to understand there’s a very, very high chance that you’re going to reject your kidney and wind up back on dialysis.”

Many patients will say, “If it’s my life or my kidney, I’m going to sacrifice this kidney. Hopefully you can get my cancer under control, and then I can be reconsidered for another transplant.” But I have a number of patients who have liver transplants. I’m stuck. I can’t give them anti-PD-1 therapy. Interestingly, you can give them anti-CTLA4 therapy with absolutely no issues. Why there’s that difference, I wish we knew, but we don’t. Then again, the efficacy of a single-agent CTLA4 therapy is far less, 50% less, than that of a PD-1 inhibitor. So I wouldn’t say no, but you really have to weigh the risk to benefits with the patient.

Immunotherapy in Patients Receiving Organ Transplantation

I really think that this is a disease, like a majority of cutaneous malignancies, that really deserves to have a multidisciplinary team manage it. Can you talk a little about how your multidisciplinary team works at Memorial Sloan Kettering Cancer Center?

Sure. When we are presented with these advanced or metastatic squamous cells, we normally bring this to our multidisciplinary cancer-management team. That consists of dermatologists, head and neck surgical oncologists, of course our medical oncologists, radiation oncologists and plastic surgeons, because we want everyone’s opinion to see how we best approach this patient and what to use first line, or thinking down the road, what would they need to later.

I do think it really helps to get everyone’s opinion because there are nuances. If there’s going to be reconstruction associated with the surgery, how will that factor in if the patient gets radiation? Will they heal? If we try immunotherapy up front, what are our goals and what are our plans later on? Bringing these patients to a tumor board is quite powerful because it gives a really nice plan, and the patient knows that a lot of people are thinking about how to best approach this.

Yeah, I agree. My patients get very excited when they know that they are at the topic of discussion.

To know that there’s a roomful of people who are really ping-ponging back and forth about what’s the best thing to do in what sequence. I agree that we do very much the same thing. Now everything has become virtual, so we actually get more participation because everybody can log in and see this. We present the slides, we present pictures and patients are very comforted in knowing so many people gave an opinion without them having to go to those multiple physicians.

Definitely. I think they really actually appreciate the amount of time that goes into their individual decisions.

Yeah, I agree. There are some people who unfortunately will not respond and develop progressive disease, metastatic disease. I guess this is more a medical oncology question, but how do you choose between palliative care and hospice or supportive care versus a therapeutic intervention? For me it really is patient dependent. It’s based on how many comorbidities the patient has, how sick the patient is and the extent of the patient’s disease. Other than immunotherapy, there are therapeutic options, like chemotherapy and radiation, we had talked about for palliation. EGFR inhibitors also can be looked at as a way to manage patients.

There are enough options that patients can be offered something other than immunotherapy if that doesn’t help. However, if you’re talking about a very old patient who you know is going to become further debilitated because of chemotherapy or because of radiation therapy, then it really becomes a very honest talk between the oncologist and the patient. What is our end goal? Are you looking to buy yourself more time? Are you looking for quality time? When it comes to my opinion, I would much rather give people quality time than being miserable for a longer quantity of time. I think most people are really on that page.

That’s when the discussion comes up between palliative care with therapy or interventions versus palliative care and supportive therapy, manage my pain, keep me comfortable and let me live out whatever time I have left in a comfortable manner at home with my family.

Multidisciplinary Management of CSCC

We want something much more optimistic. Where are we going with this disease? Where do you see the future of treatment options for patients evolving now that we have some cemiplimab in our arsenal of therapeutic options? What are your hopes and expectations for where you expect therapy or management of cutaneous squamous cell to be going?

That’s a great question. As a dermatologist and a Mohs’ surgeon, I always think of trying to get these lesions as early as possible or even be more preventive in my approach to the patient. Especially in our organ transplant population, if we can switch their immunosuppression from something that we know is very causative of future squamous cell carcinomas—like the calcineurin inhibitors, if we can get them on an MTOR inhibitor&mdash;we know that has a decreased risk of cutaneous squamous cell carcinoma. Trying to be proactive in our approach to prevention is always exciting for me.

Now that we are still seeing advance in metastatic squamous cells, knowing that we have a form of immunotherapy like cemiplimab is helpful for us to know, because for patients who may have an increased morbidity from surgery and radiation and are still leading active lifestyles may not want to undergo all that, we do have this new option, which is really important for us to consider.

Yeah, I agree. And it’s not 100% effective; it’s 50%. But that’s an amazingly good cornerstone to start building on, looking at whether we can add EGFR receptor inhibitors to cemiplimab to increase the efficacy. We’ve got some investigational agents that are injectable into the tumor. Can we use that to create more of an immunologically driven environment in conjunction with cemiplimab to get better cell kill? There are so many exciting future options. Can we use radiation and cemiplimab together to get more bang for our buck? That’s another question being looked at in clinical trials.

So I think the number of clinical trials are really exponentially increasing every day when it comes to cutaneous squamous cell because there’s so many options and I think we need to now push that needle from 50% to 75% and hopefully in our lifetime we can get it pretty darn close if not to 100. But I think when it comes to how do we impact it most, I think awareness and prevention is clearly where we need to start, although we have these therapies, I hope there’s a time in my life where I don’t have to talk about therapy and I can go out there and just talk about education and prevention.

For sure. I think these off-label neoadjuvant or off-label adjuvant trials might really be helpful and hopeful.

I hope everyone enjoyed that as much as I did. Thank you, Dr. Rossi, for such an informative and stimulating discussion. And to our viewing audience, we hope you found this 

® program to be useful informative as well. Thank you.

Thank you, Dr. Pavlick, for being such a wonderful colleague and so information rich.

Considering Immunotherapy for Cutaneous Squamous Cell Carcinoma

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