Clinical Approach to the Diagnosis & Management of aCSCC and aBCC

In this roundtable session, expert dermatologists describe current diagnostic approaches and risk factors for disease progression in advanced cutaneous squamous cell carcinoma (aCSCC) and advanced basal cell carcinoma (aBCC). This discussion covers the latest guideline recommendations for treating patients with aCSCC and aBCC and highlights key takeaways from recent clinical data on therapies such as neoadjuvant therapies.

This is Part 2 of 3:

• Part 1: Disease State Overview of Current Advanced Nonmelanoma Skin Cancers
• Part 2: Clinical Approach to the Diagnosis & Management of aCSCC and aBCC
• Part 3: Clinical Challenges and the Evolving Landscape of aCSCC and aBCC

Dr Todd Schlesinger: So let’s talk about Theme 2. So Theme 2 in our presentation today is the clinical approach to the diagnosis and management of advanced cutaneous squamous cell carcinoma and advanced basal cell carcinoma. And here, this is designed to talk about what our clinical approaches are to diagnosing these patients, talk about some of the risk factors, how are managing the patients generally – thinking about the guidelines, of course the NCCN guidelines, we talked about that as well. And then we'll talk about neoadjuvant cemiplimab as well, because there's some recent data that's come out about using cemiplimab in neoadjuvant setting for cutaneous squamous cell carcinoma.

So first off, let's talk about the clinical approach to diagnosing these patients. I think we've covered some of that. Dr. Kaufmann, what's your approach?

Dr Mark Kaufmann: Well, I think, obviously, you see someone that you believe has a cutaneous nonmelanoma skin cancer, you're going to do a biopsy, and you're going to send it for H&E, and when you get it back, then you have basically to determine what you're going to do with it based on all the risk factors that we've been talking about.

Dr Aaron Farberg: I'd like to chime in right there. Part of the issue is simply when people go to biopsy these lesions, they'll often get just a tiny little biopsy just at the edge.

Dr Mark Kaufmann: Right.

Dr Aaron Farberg: And so if I can do a public service announcement to all my colleagues and all the dermatology colleagues that we have out there, it’s do a high-quality biopsy. We have lots of data to show that there's a significant amount of upstaging that occurs from the initial biopsy to when you have the definitive treatment, whether that be Mohs or a wide local excision. And that really does matter. Getting that diagnosis right, the point is, is when you do a tiny little shave off the side, you're never going to get perineural invasion.

Dr Mark Kaufmann: I couldn't agree more, and I actually will typically, for when I suspect a cutaneous squamous cell carcinoma will do a punch biopsy in order to get a good depth and a little more information on that.

Dr Todd Schlesinger: And then on that, we expect our pathologist to give us a report that reflects the true accuracy of that specimen, which may even come in the form of a synoptic pathology report, like we're used to seeing from melanoma, where we actually see those risk factors laid out, or those characteristics of that tumor laid out, including depth, if you have a biopsy that's capable of that.

Dr Harrison Nguyen: So Dr. Kaufmann, I'm so glad you brought that up, because really we need, to make that accurate diagnosis, we need to see the dermis, right? And so a lot of these lesions are very hyperkeratotic, and it's frustrating to see a biopsy where it's just of the

Dr Mark Kaufmann: The keratotic region.

Dr Harrison Nguyen: Yeah, exactly, and that may lead to delayed diagnosis. And so for me, when it's very hyperkeratotic, after numbing it up, I take off that keratotic layer so that I can make sure I can get that appropriate biopsy so that we can visualize the dermis. And so that the pathologist can say, you know, if there is poorly differentiated features, we can immediately start managing them appropriately.

Dr Todd Schlesinger: And so when you get that biopsy, what are you looking for? The risk factors that help you decide what to do next are what?

Dr Harrison Nguyen: So having the differentiation, so poorly, moderately, and well-differentiated, that's important to me. I think a little bit about depth as well, but I don't typically get that information from a biopsy. I typically get that from the debulker during a Mohs procedure.

Dr Aaron Farberg: Nobody can even decide what depth matters. Is it 2 millimeters? Is it 6 millimeters? Is it down to the fat? I mean, again, this is what I meant at the beginning when I said this is like Texas. It's the Wild West. Everyone can kind of make their own decisions.

For me, I take a lower threshold. I say, “Hey, if it’s 2 millimeters, that’s something, that’s important.” Another thing I’m trying to get as much information from that report as possible, and you mentioned this, a synoptic report would be fantastic. Wouldn’t that be great to standardize just like we did back in the – for melanoma? Hopefully we'll get our dermatopathologists to move in that direction. I know many of them already have, but size, for example, gets included in that. I'm always paying attention. It's usually listed in the path report, as they measure it when they gross it. And that's a figure that even though it may not be technically part of the histopathology, it's still part of that report.

Dr Todd Schlesinger: And that size could be a little bit different, and the histopathology may be different than what you see in clinically. So we measure the clinical size as well, photograph that and document.

Dr Aaron Farberg: And based on the location, which is also listed; a 2 cm on the scalp is different from a 2 cm on the lip, from the cheek, and on the back. So again, you have to take in all the different features that are unique to this patient.

Dr Todd Schlesinger: And I think speaking of those risk factors, when it comes to size, the NCCN and other guidelines treat that differently. NCCN seems to be very conservative. I think it's a 6 mm, we'll talk about it later, but a 6 mm size puts you in a high-risk category. Any one of these multiple factors automatically upstages you to a high risk per NCCN, but that may not be the case for AJCC and BWH. So I think we have to use these guidelines together as a whole.

Dr Aaron Farberg: And then even when, to dive a little bit deeper into those NCCN guidelines, there's been a recent update. So it's exciting that, hey, a year ago, they really changed them up a bit. And the focus went from low-risk to high-risk to, hey, now you've – let's split up this and stratify this high-risk group into high-risk and very high-risk.

And then you might ask, well, what's the clinical implications of those? And you realize that the high-risk group, those are going to be ones that you’re worried about for simple recurrence. But we all know that’s not what we’re all worried about. I’m worried about which ones are going to metastasize, because that’s very much going to drive what our management is going to be.

Dr Todd Schlesinger: That's key. That's key as well. Okay, so presentations from early-stage manifestations versus advanced stages of these carcinomas. I think we've covered most of these things here. We talked about risk factors, clinical presentations, the diagnostic criteria to use when diagnosing these patients. I think we've covered most of it. Do you have any other thoughts about the clinical presentations of these patients before we move on?

Dr Aaron Farberg: I'll throw another topic out. What do you think about basal/squamous? How do we define those? Where do those fall into the category? It's always been a struggle for me. That's... I'll tell you one of my theories is that they're really all basal cells that then cause squamous differentiation. So depending upon where you're biopsying, you're going to get either a squamous and then maybe get a basal cell and then it's all in between. What's your experience been?

Dr Todd Schlesinger: My opinion on those is, well, first of all, I think they're higher risk in a general sense because you've got, to some extent, I put it in the risk category of at least moderate differentiation to poorly differentiated when I see those tumors occurring in the same specimen, so that's how I think of them. As far as the pathogenesis, I'm not really sure what's happening. I mean, my thought is that basal cell carcinomas arise from the interfollicular basal cells in the epidermis, and squamous cells that are rising somewhere in between there, above, but I don't think we really have a clear idea of what's really happening. So, I just think about them as being higher risk.

Dr Aaron Farberg: Fair enough. All right. Well, what about locally advanced basal cell? What's that term? What do you consider to be an advanced or locally advanced basal cell? I know there's obviously a definition that was created for the clinical trials, but we're in the real world here. We're seeing patients. What do we all think about as locally advanced or advanced basal cells?

Dr Todd Schlesinger: I mean, I define that clinically. Primarily, it's my ability to resect that tumor without excessive morbidity, mortality, and that's really also involving the patient because in that case, the patient's opinion about what they want, what they're willing to tolerate as far as surgery also, I think, comes into play as well.

But can you cure that patient with surgery without causing excessive morbidity? Can you cure the patient with radiation without causing damage?

Dr Mark Kaufmann: So you're looking at the whole picture.

Dr Todd Schlesinger: The whole picture.

Dr Mark Kaufmann: The whole picture.

Dr Todd Schlesinger: It's more of a clinical, in my opinion, it's more of a clinical definition than simply looking at the tumor and saying, “Okay, that's big, that's locally advanced.” It's really more about what are you going to do about it? That's my opinion.

Dr Harrison Nguyen: Dr. Schlesinger, I agree with you. I think most of it, for me, is a clinical impression. Although there is also a pathologic component, if I see perineural invasion, then it's also an advanced basal cell.

Dr Aaron Farberg: Have any of you guys seen metastatic basal cell in your careers?

Dr Harrison Nguyen: I have.

Dr Aaron Farberg: You have? All right. I've seen one.

Dr Todd Schlesinger: Yeah. Mine was in residency.

Dr Aaron Farberg: Yeah. I think infiltrative basal cells are another one that you know perks up a number of red flags for me. Part of it is just knowing going into the procedure, usually the Mohs or a wide local, that this is going to a more complex lesion. And I need to think about my toolbox and all the different options that I have out there besides just my 15 or 10 blade.

Dr Todd Schlesinger: How about multiple tumors? If a patient comes in that walks in with 10 or 15 basal cells or squamous cells, does that put them into an advanced category?

Dr Harrison Nguyen: Yeah, and it depends on the age too. If they're younger, then I'm starting to think about a syndrome. But if they are, they have multiple basal cells and let’s say they’re an older patient, that's going to be -- it's going to be a factor of what we talked about with a clinical impression of where are these tumors? How big are they? What type of morbidity are we going to encounter with treatment?

Dr Todd Schlesinger: Right. And then in metastatic or in-transit metastases, regional lymph node metastases from those tumors and of course metastases, so the definition how would you define, how would you think about when someone says to you this tumor has in-transit metastases, what would you sort of think about there, what would you say?

Dr Harrison Nguyen: For in-transit metastases?

Dr Todd Schlesinger: Yeah, how would you define an in-transit metastasis?

Dr Harrison Nguyen: If the tumor has, is in path to the lymph node basin, then that's in-transit metastasis . And so for me, I'm glad that you brought that up, because if I see these advanced or high-risk squamous on my clinical impression, I do a nodal exam. And if I feel anything clinically, then I'm going to be sending them for imaging.

Dr Aaron Farberg: Public service announcement number 15, I think, for already—

Dr Todd Schlesinger: Nodal exams.

Dr Aaron Farberg: Do a nodal exam. Oh, my gosh. If we could get our dermatology colleagues to do a high-quality nodal exam every single time, I think we'll save a lot of lives. And I think we're doing a very good job. It's really just a good reminder to perform these exams each and every time.

Dr Todd Schlesinger: That's what I do in my clinic, my full-body skin checks, I do nodal exams on them and they're documented every time. So that's something that I think is very important as well.

Any other thoughts on your approach to diagnosis and management of advanced cutaneous squamous cell carcinoma or advanced basal cell carcinoma before we move on a little bit more? I think we've done very well. I think it was a good discussion.

Okay. So anything new in the diagnostic approach? So who's using, anybody using any type of augmented intelligence applications in the clinic for these tumors?

Dr Aaron Farberg: Well, we're definitely utilizing new technology, electrical impedance spectroscopy, for the melanoma side of things. That's a device that sends an electrical signal through a nevus or a mole to see is it likely to be a melanoma or not.

It hasn't quite expanded or been FDA approved for nonmelanoma skin cancer, but under research protocols that's what they're looking at. There was a new spectroscopy device that was recently FDA cleared, and again, I have to highlight that this is just a clear, not an FDA approval, so the bar was much, much lower. And it was designed for primary care physicians of all things, or primary care clinicians to utilize this device. And, it has a binary outcome of monitor or investigate further.

Dr Mark Kaufmann: I think most of the devices are being developed for the melanocytic lesions. I don't know of many that are being developed for the nonmelanoma skin cancers as much, but as far as imaging is concerned, certainly confocal microscopy has been used to help image with basal cells and squamous cells if you have access to it.

Dr Todd Schlesinger: And of course, more body imaging we're using to diagnose our squamous cells and basal cell carcinoma including ultrasound, lymphatic ultrasounds, and I still think the jury's out on that. Anybody have a different opinion, I think the jury's out on it? Of course, we can use CT standard contrast CTs, PET CTs, things like this we're used to using to try to evaluate for an old disease or a metastatic spread for both basal and squamous cell carcinoma.

Okay, so we're sort of at an emerging point there. And then biopsy technology, then we covered a little bit about biopsy technology earlier in gene expression profiling, but that's something that can help us assess risk as well. All right, all right, so nothing else there.

All right, so let's talk about treatment. So what this is really designed to do is sort of capture our clinical approach to patients with advanced cutaneous squamous cell carcinoma, advanced basal cell carcinoma. What are the things that make us… influence our treatment decisions and how do we assess, in the general sense, all the options for our patients and then we're going to speak a little bit about neoadjuvant treatment. So it would include hedgehog pathway inhibitors, epidermal growth factor receptor inhibitors, never approved for squamous cell carcinoma but still used a lot, intralesional therapies, those are things that are being looked at investigatively, oncolytic viruses, of course more for melanoma but being looked at in nonmelanoma skin cancer as well.

So I guess just talk about briefly your approach to a patient that comes in that you've actually looked at them, and they've got, for example, squamous cell carcinoma on their face or whatnot. You've already determined this is locally advanced, you're already thinking surgery's not an option, or, what's your next step? What's your first thing you would think about for treatment, what would you do next?

Dr Harrison Nguyen: Well, as a Mohs surgeon, I'm a big believer in using Mohs surgery (laughing) for treating SCC and BCC. Of course we have appropriate use criteria that helps guide us in terms of the types of tumors that would be amenable to it, but for advanced ones, ones that have the features that we've talked about, as, once it presents to me on day of Mohs, I get a lot of data that day. I get the depth, I am able to see if there's any perineural invasion, I get the differentiation, and that may trigger for me at that time to determine whether we need to escalate care or involve other providers or to get some imaging. And so, Dr. Farber mentioned earlier about gene expression profiling. If they have any high-risk features or advanced features, then I will get gene expression profiling. And if I'm not able to get clear margins, then as a Mohs surgeon, that's when I reach out to my collaborators, radiation oncologists, medical oncologists, to help with treating these patients.

Dr Aaron Farberg: It's a very important point. I think at all times we always have to remember we should be treating every patient in a multidisciplinary fashion when it's appropriate. Most of the time we don't have to call any of those other colleagues or friends, but to always consider it, it's a very important point.

Dr Todd Schlesinger: And then sometimes these patients may come in to the office from the outside. Maybe they haven't had access to care for a long time, and they unfortunately come in with already an advanced tumor where surgery may not be an option for them or could be very disadvantageous to the patient to attempt a large surgery. So what about those kind of patients where, yes, of course, we always want to go for a clear margin if we can get one. What's your approach to that patient where you look at that and you're like, I don't think… this is not going to be a surgical candidate. What's next?

Dr Aaron Farberg: Right, well, again, yeah, you always have to highlight surgery as your initial treatment. But if that's not going to work, then really you have to start thinking not outside the box, but all the different tools that we have. And that includes things like radiation therapy, SRT (stereotactic radiation therapy), also a very appropriate treatment and has been shown to be very effective, and patients enjoy it and it's well tolerated.

Beyond that, you can also think of even topicals. There's a variety of different ways that I've utilized topicals to treat patients. Does it have the same cure rate as Mohs or SRT? Absolutely not. But think about the patient that, as you mentioned, is just not appropriate for surgery. Maybe they're 95 and they still have many years ahead of them, but they just don't want to go through a surgery. They don't want to go through radiation. What are those other treatment options? There are topicals, but now we have even, well, we've had even better options. Utilizing a hedgehog inhibitor and PD-1 pathway as well, we have immunotherapy that works very well.

Dr Harrison Nguyen: Dr. Farber, have you ever used PDT (photodynamic therapy) to shrink a tumor prior to surgery?

Dr Aaron Farberg: Yeah, it's called throw in the kitchen sink. Yes. PDT, topicals, it's a combination of different treatments, oftentimes one isn't going to be enough. I'll usually, as we are getting to more locally advanced or high-risk subcutaneous squamous cell, that's when we have to really break out something like cemiplimab, whether that be in a neoadjuvant or adjuvant setting or as a simple treatment setting. And then also, of course, consider hedgehog inhibitor as well. And there's two of those that can be utilized. The important thing here is that these patients need a cheerleader. They need somebody to really encourage them to go down this pathway of treatment. Because even though overall these treatments are well tolerated, there's still a number of side effects and adverse events that we have to usher them through.

Dr Mark Kaufmann: I think it's important to start thinking more about neoadjuvant treatments, because we're always talking about, are we going to send this patient for radiation after doing Mohs? But we have to consider that the neoadjuvant treatments say with the checkpoint inhibitors will allow your own body to actually start fighting this tumor, which I think is always a great idea is to let the person's immune system do some of the heavy lifting before we do something more definitive.

Dr Harrison Nguyen: We're cheerleaders, but we're also quarterbacks too. We are the quarterbacks of these skin cancer patients. And so we recognize as dermatologists and Mohs surgeons, we understand the staging, we understand high-risk factors. And so that's, as the quarterbacks, we're able to then coordinate care when needed.

Dr Aaron Farberg: This is a really exciting time to be here, because we've got a number of different treatment options. I'm just thinking about a patient already that I saw last week and they have a high-risk squamous cell that literally covers their entire nose. And again, you know, as a Mohs surgeon, we can heal with steel and we can cut off somebody's entire nose, but I really don't want to do that. And we know that that's not the best treatment option for that patient.

And so, already in discussions with the patient, I have a medical oncology colleague just down the street and we're going to do neoadjuvant cemiplimab. and we're going to shrink that tumor down, and as the studies have shown, it's likely to be very effective, and we'll even see if we have to do a definitive surgery. We might, but I can pretty much guarantee it's going to be a lot smaller and a lot less morbidity. This is the right thing for these patients.

Dr Harrison Nguyen: Dr. Farber, can you talk about setting up that collaboration with medical oncology? So this is, we talked about cemilpimab in a neoadjuvant setting. It's not currently FDA approved. However, we have strong data to show it. Can you talk about that collaboration, how you're able to convey that and structure that?

Dr Aaron Farberg: Yeah. Well, as an assistant program director with a residency program, I'm always coaching and teaching my residents. And as soon as they get out into the real world, you need to figure out who your friends are. And that's that multidisciplinary approach, which is so critical. It's so important to treating these patients. You want to identify medical oncologists, surgical oncologists, radiation oncologists. That's your team. Because we all recognize that each one of us have certain skills. You have certain surgical oncologists that are going to operate as much as they can. Medical oncologists will sometimes think out of the box, and that's where you need one of these medical oncologists that will say. "Hey, let's go ahead, let's do this for the patient."

Dr Todd Schlesinger: And I think that also brings up, had you mentioned some of the adverse events that we can see with immunotherapy generally will tolerate and sometimes they can be more severe, and I think one of those things is some of those adverse events can present as common diseases like cough and diarrhea, maybe shortness of breath or maybe a rash. Things that you wouldn't, maybe your front staff wouldn't normally think about as being a dermatological condition.

So I think in my practice what I've always taken to, and I always teach this, is also to go to your front staff and tell them about immunotherapy and say these are patients that are, they may not even be infused or injected in the office, but they're being treated by the oncologist down the road, and they may call these lists of patients, may call with certain symptoms. And then you can be aware of that, it's important to intervene early and manage those adverse events early so your front staff can't say, you know, that “We’re dermatologists, you need to go to urgent care for your cough.” (laughing) So, this is what they'll say.

Dr Aaron Farberg: Back to us.

Dr Todd Schlesinger: Yeah, come and see us and we manage those things early. So we're really collaborating on the management of the adverse events and monitoring them together.

Dr Aaron Farberg: This is one of my favorite parts of treating these types of patients is actually helping colleagues treat these types of patients. And what you highlighted is what I highlight for my colleagues as, these are all the -itises. It's the pneumonitis, colitis, dermatitis. It's all these -itises that happen because with cemiplimab, which we're talking about here, the receptor is pretty much all over our body in all the various cells. So you're going to have different adverse events. And what I want to highlight, though, is for the most part, most of these adverse events, were low grade, right? They didn't really impact the patient. And the way that I know that is if you look at the patients that actually were discontinued from the drug, this is less than 1% or 2%.

Dr Todd Schlesinger: Small numbers.

Dr Aaron Farberg: It's a small number. So patients wanted to stay on this medication. And again, we have a nice label that goes along with it that we actually know how to utilize this drug, what are the lab abnormalities that we're actually looking for, and we have a good guidance as to how to carry this forward.

Dr Todd Schlesinger: And as we've had patients on this drug for a long time, we've learned that they need to stay on it for a while in order to get the best outcomes with that medication. The other thing I do speak to my patients though, clearly about, although most adverse events are well tolerated and not severe, there's a few that are sleepers that can be more severe that can actually survive, even the patients being off, stopping, discontinuing this medication, those are the more rare ones, cardiovascular, neuroendocrine adverse events, diabetes, very rare, thyroid disease, hypophysitis or pituitary inflammation, adrenal inflammation so they can create acid disease or other things can happen. So these endocrine, I also, I would add that I always keep an endocrinologist on my speed dial as well...

Dr Aaron Farberg: I have one of those.

Dr Todd Schlesinger: …because those adverse events come up, you need to address them even faster.

Dr Mark Kaufmann: And they last longer too, right?

Dr Todd Schlesinger: They can stay. They can survive not only, they can show up delayed, even after they're off medication, but they stick; they’re more likely to stay with the patient long-term.

Dr Harrison Nguyen: That’s something I was interested to learn from my international colleagues is that dermatologists in, for example, in Europe will commonly manage and prescribe themselves these checkpoint inhibitors, and so do I think that's going to happen here in the US? I mean, we can barely get our dermatologists to comfortably prescribe biologics. And so I don't see derms developing a lot of traction in prescribing cemiplimab and these other neoadjuvant therapies. But it's important for us as a field to understand its role, its role in neoadjuvant and adjuvant therapies, so that we can be able to counsel patients and get them the right care.

Dr Mark Kaufmann: I think you might find some dermatologists starting to do them. Infusions.

Dr Aaron Farberg: Yeah, there's a handful and I'm hoping to get my own infusion center open too.

Dr Todd Schlesinger: Yeah, I think it's exciting. I mean, you have to have a certain set up, pretty much what the oncologist would have. So if you are interested in doing infusions, you might just want to go and see your local oncologist and see what they're doing because they're likely to be following all the recommendations for the chemotherapy that you now have to follow for cemiplimab.

Dr Aaron Farberg: Which also highlights, though, I think, a reason why many dermatologists will prescribe a hedgehog inhibitor, because it is something a little bit more approachable for the dermatologists. They can prescribe it from their office and we utilize hedgehog inhibitors as well.

Vismodegib and sonidegib, they’re 2 really fantastic hedgehog inhibitors. I feel like, as of recent, I've shifted over more to sonidegib just based off of the efficacy and really the tolerability. That's been the key aspect, and I think I like most people are utilizing different treatment regimens as opposed to what's on label.

Dr Mark Kaufmann: Pulse therapy.

Dr Aaron Farberg: Yeah, and pulse therapy.

Dr Todd Schlesinger: Pulse therapy. Other things we can do to help mitigate the patient's adverse events with those medications and, of course, and some data has already been published by this, global safety data has shown that some of those adverse events will wane over time. Of course, some of the patients will go off it as well, but the ones that stay on it, their adverse events may wane, so it's encouraged people to stay on it longer and to get the outcomes we're looking for.

Okay, anything else you can think of when it comes to, I think we've done very well here. Let's talk about staging. We've spoken about staging to some extent already. We have in place, for squamous cell carcinoma, AJCC 8th edition staging criteria as well as the Brigham and Women's Hospital staging criteria as well, which are very different. And of course, the AJCC starts with size, tumor size, and then depth of invasion are things that it looks at, whereas BWH looks at risk factors and how many risk factors there are in order to decide what the stage is.

So anybody, give an opinion on how you use these in your practice. How do you use staging criteria? Do you use it? Do you think of it? Do you not use it?

Dr Aaron Farberg: You got to be honest here, guys. Who's using staging with their squamous cell? I think I've lectured on this many times before, and I would say most of us are not clinically staging these patients regularly. And you don't have to. Oftentimes it's very straightforward. You're able to cut it out and move on in life.

But when you do get some of these high-risk factors, then you really do need to stage it. And, you know, pick your staging. Some people like Brigham and Women's, which is 4 major criteria.

Others, it's AJCC8, which is based primarily off of size and depth. I think most people use a combination of both, as well as some other Gestalt and high-risk features. And that's kind of what I do. I like Brigham and Women's, but I do care about immunosuppression, for example, and include that in my staging.

Dr Mark Kaufmann: I agree. It is a Gestalt. There's not one that's going to solve for everything. I like the Brigham and Women's myself because of the way that the T2A and T2B actually really show a large difference of the way that the patients are going to do in the T2B category.

But that doesn't solve for everything. And size, in AJCC, I don't think, is really a great factor either. And the genetic profiling bears that out, that it doesn't always work the way it's supposed to.

Dr Todd Schlesinger: Speaking of immunosuppression, or even solid-organ-transplant patients, clinical thoughts on the utility of a checkpoint inhibition in that subset of patients. And I'm also thinking about patients with not only solid-organ transplants, but other immunosuppressive chronic conditions such as CLL, even HIV. So these are all things we think about because the studies for basal cell and squamous cell carcinoma didn't include these patients.

Those patients were relatively healthy. Many of them had prior therapies before, but they were healthy patients who were walking, talking, doing very well, generally not immunosuppressed. So any thoughts on the utility of these medications in these even higher-risk patients?

Dr Aaron Farberg: I would say it's at least worth a try. You know, these are very complex patients that are usually at the end of their therapeutic ladder and there's not too many options, which again highlights the importance of the options that we do have. They came from a lot of research and development, and thankfully we're committed in developing more of these types of medications so that there will be other options for these patients.

Dr Todd Schlesinger: In fact there has been some data that's been published that shows that in HIV patients they really don't behave much differently as far as their efficacy and tolerability than the normal population. Especially now in view of the fact that we're we've got such good anti -retroviral medications out there. So people that are very well-controlled with HIV. So, okay, good.

All right, anything else on staging that you guys want to add?

Dr Aaron Farberg: I would just highlight again the inherent limitations of staging and that you can't just go to sleep and not worry about these types of patients. There are those that will otherwise be considered low risk that go on to have bad outcomes. And we always need to figure out a better way of identifying these patients. Because again, if it was your family member you’d absolutely want to know.

Dr Todd Schlesinger: I think the other adverse effect I wanted to mention while we're here talking a little bit about PD-1 inhibition is fatigue. Fatigue is mentioned clearly in the basal cell carcinoma data and the squamous cell carcinoma data, and I’ve had patients who I find that to be an issue for, in the absence of any abnormalities. Of course we're checking laboratory tests before their infusion every time and monitoring adverse events and checking for metastases and tumor progression, and all these other things. But at the same time, fatigue can sometimes creep up on people, especially older patients, without any abnormalities in their labs. So I just wanted to highlight that as something I really keep an eye on and I talk to them in advance about it.

Do you guys have any other thoughts or different thoughts about that?

Dr Harrison Nguyen: I'm glad you brought that up. In the phase II trial, fatigue was the most common adverse event. But to Dr. Farber's point, by the time that we are reaching for these medications, it's warranted, and so we try to coach them through, try to cheerlead them through the fatigue, but it does happen.

Dr Todd Schlesinger: So, you know, for the audience, what we're looking at here, we are all taking a look at the NCCN guidelines for a cutaneous squamous cell carcinoma. This is the very high-risk cutaneous squamous cell carcinoma algorithm that we're looking at, which is available, that could be looked at online. But any more information that comes to mind when you're thinking about NCCN guidelines when it comes to new adjuvant therapy, tumor growth, perineural invasion, when you look at this algorithm, anything else you're thinking about?

Dr Aaron Farberg: I would just highlight that these guidelines are like this wide. You can drive a truck through them. And they're that way purposefully, because at the end of the day, you're the clinician sitting down with your patient, and part of those guidelines also tell you to individualize this patient's care. And so you have a variety of different treatment options and a variety of different ways of staging and understanding these patients' risks, all for the same purpose of aligning that management appropriately with the risk for that patient.

Dr Harrison Nguyen: Yeah, I just want to highlight that this is, neoadjuvant therapy with cemiplimab is part of the NCCN guidelines. And so I think that that is a, it's based on the phase II trial and the data that was that was seen in it. It achieved pathologic clearance in 50% of patients. And these are tumors that were amenable to resection as well. And so it's important that derms recognize this and that this is an important emerging therapy to move forward for our patients.

Dr Todd Schlesinger: And that can be very different from radiological improvement, because you're more likely to see that improvement on pathology and radiology and radiographic analysis may not show the same improvement that you would see pathologically. So this is very important data that we get and that we're able to do a biopsy and determine whether or not that tumor has cleared or at least improved based on the biopsy.

Now sometimes in the studies, of course, the patients who had metastatic disease and cutaneous disease as well, both, you had to look at both the RECIST criteria, response evaluation criteria, and solid tumors when you're looking at the scans and then the WHO criteria when we're looking at pictures. So we really had to combine those two things together.

The other thing that I find very interesting about the NCCN guideline is what you do with these patients who have negative margins. So negative surgical margins, but high-risk factors. So what do you do with those patients? I think that's where, and I'm curious to see what everybody thinks on the adjuvant radiation therapy in that setting. Any thoughts? I think the literature in my opinion is all over the place and there's really no clear definition of what we should be doing with these high-risk patients, clear margins, yet high-risk factors.

Dr Mark Kaufmann: I would just say that the criteria says to consider adjuvant radiation therapy, and I can just tell you that if you send them to a radiation therapy, they're going to get it. So consideration is done at that point.

Dr Aaron Farberg: Well, that highlights an important part of, as the dermatologist, you are the gatekeeper. You may not be doing the radiation therapy, you may not be doing that sentinel lymph node biopsy, but you are sending them to the appropriate referral if you feel that it's appropriate.

You can have that discussion with the patient prior, which is why it's important for us to understand what all these different treatments are. Radiation is a very important topic that I would love to hear a bit more on what everyone's doing.

Who are you radiating? There's the obvious, okay, when you see perineural invasion, how often are you seeing perineural invasion? Probably not that often, but you're radiating more patients. Who, what, where, and why, and I'll tell you what my thoughts are.

Dr Todd Schlesinger: Go ahead.

(laughing)

Dr Aaron Farberg: All right, well, so it's interesting because I have a new paper that was recently accepted exactly on this topic. And the reality is, in the study, we found that people are being radiated for every reason you could imagine.

One might say it's perineal invasion, one might say it's size. And the bigger concern is that we know that radiation helps, but we're just not sure in which patients it's going to help the most. And one of the things that we were able to identify was looking at a GEP (gene expression profiling), looking at the molecular makeup of these tumors.

And in the very high-risk patients, the ones that got the highest risk score, they actually did benefit from radiation. You'd still consider, of course, we hate that term "consider," but you'd still consider it for the other patients. Again, you're not limiting patients that would otherwise would still benefit, but at least you find a utility and you know that in these very high-risk patients it would be beneficial.

Dr Harrison Nguyen: The two tools I really rely on, so I really do use the Brigham and Women's Staging. The data does show that it's superior to the AJCC from a positive predictive value specificity in that it does predict risk for local recurrence, normal metastasis, and it's better than AJCC. And so for me if it's a T2B, that's when I really need to integrate the GEP data.

And if the GEP data shows that it is a high-risk tumor genetically, then I'll send to radiation oncology. But I'm a Mohs purest, where I did my training, if we did, if we got clear margins, no patient was going to get radiation. Now, I have now transitioned my practice, now that I've integrated GEP and, in my experiences. So, I do do, even with negative margins, if they have a high genetic profile and they have enough of the Brigham and Women’s risk factors, then I’ll send them for radiation.

Dr Todd Schlesinger: Very interesting and very controversial topic. So, we're going to see a lot more good data coming out on that one, because it really is a, it’s almost in some cases, when you think about will that supersede our thoughts on perineural invasion? Because in some cases, you do Mohs, you may do a biopsy, then you go and do Mohs surgery, and you find perineural invasion. And then the NCCN guidelines call… they use the word extensive. And somewhere in the footnote, they define what that means.

Dr Aaron Farberg: And the data can be murky in that sense, too. In some cases, perineural invasion is important. In other cases, in multivariate analyses, it drops out. And it makes sense, too. Because if you think, if you have a very large lesion, well, that's probably more important than identifying perineural invasion. Because if it's this big, odds are there's a nerve this big that's in there. Do you really have to go and find it? No, you don't. That's the point.

Dr Todd Schlesinger: Okay, so continuing NCCN guidelines for neoadjuvant therapy with cemiplimab, so I think we've talked about this quite a bit. Multidisciplinary discussion is also called out frequently in the NCCN guidelines, which I think we've all talked about is critically important for our patients, especially when there's big treatment decisions being made and flexion points in their care where you're going to be making a decision, do I go A or do I go B? And so that in mind, there are the recommendations are there for basal cell carcinoma as well and you've got the Category 2B recommendation for the hedgehog pathway inhibitor vismodegib, for sonidegib and then for cemiplimab as well, so that's all called out for the various locally advanced diseases. You've got neoadjuvant mentioned as well, which is new coming into the guidelines. So any further thoughts about how you would utilize NCCN guidelines for basal cell carcinoma when it comes to neoadjuvant therapy with either hedgehog inhibition therapy for basal or for either one PD-1 inhibitor immunotherapy?

Dr Aaron Farberg: I think it's just important to remember that you have all of these tools in your medicine toolkit. Oftentimes it's very easy to simply just refer these patients, but recognize you're doing the initial biopsy oftentimes and making the initial diagnosis. So these patients are very much attached and paying attention to you, and understanding the full treatment landscape is going to be very important.

Dr Todd Schlesinger: Any other thoughts?

Dr Harrison Nguyen: I agree with Dr. Farber.

Dr Todd Schlesinger: Very good. All right. So, a couple more key questions here are, and I think we've covered most of this, I think we've done very well talking about the guidelines themselves, how they reflect our treatment approach, and are we using them. I think we've done that. The updates, we mentioned a little bit about the key updates that are coming into the new guidelines as well. Any further thoughts on the updates this year?

Dr Aaron Farberg: I mean, just remember that guidelines are often behind. They're not always the most up-to-date in regards to what the literature is saying and not always up-to-date with what the community is actually performing. So, guidelines are not written in stone. They're not something you follow to the tee. They're designed to give you guardrails that we can then practice medicine in between.

Dr Todd Schlesinger: Okay. So, as far as immune checkpoint inhibition therapy in the current landscape for patients with advanced cutaneous squamous cell carcinoma and advanced basal cell carcinoma, I think we've covered it pretty well. This slide that we're looking at is simply showing us the mechanism of action I think we all know, but the simplest way that I explain this is uncloaking, I like to use my Star Trek Enterprise (laughing) theory and that these tumor cells have figured out a way by expressing these ligands on their cell surface to hide themselves from the immune system.

Basically, the tolerance immune system, sense of self. And if we block this checkpoint, we can have T cell infiltration. I think that's important to think about, though, when it comes to why neoadjuvant therapy might be working as just a theoretical, that you have tumor infiltrating lymphocytes in the tumor bed, that if you can activate those in advance of doing surgery, because if you do surgery first and then you treat in an adjuvant setting, then you're removing those potentially helpful tumor-infiltrating lymphocytes. That's just a theory of why it may be working for us in the neoadjuvant setting, but it makes sense to me clinically. Any other thoughts on the pathogenesis of neoadjuvant therapy, why it works?

Dr Aaron Farberg: Yeah, my analogy is that cancer develops a secret handshake to tell our T cells not to kill it and so by blocking that, well then you recognize cancer as the bad guy and you're able to take care of them.

Very well. Okay, so we're getting close to wrapping up here so prioritizing treatment goals and patient preferences in the context of advanced disease, we've talked already I think well enough about the multidisciplinary approach we use. One thing I highlight when it comes to multidisciplinary approaches, how different it is, and I think everybody here has highlighted the difference between the academic setting and the private practice setting that we have to create, we're all in private practice and we have to create this multidisciplinary team on our cell phones. We have to get these people, we have to make friends, so if you're a new physician coming into practice for the first time, out into practice, that you've got to reach out and make friends with people in your community. And it's not something, these are not diseases you practice alone with, so you want to involve your colleagues in these patients. Any further thoughts on that?

Dr Aaron Farberg: Yeah, I think if you highlight what are treatment goals, it's actually, this is a critical point when you're discussing hedgehog inhibitors or  cemiplimab PD -1 The reason being is that when you look at the efficacy data, and again, this could be immunotherapy or it could be hedgehog inhibitors, the efficacy data is not fantastic. We're not talking about 50% overall with complete responses. At first you might think, "Well, gosh, we're not doing a great job," but actually we are, because what are your treatment goals? It should involve quality of life.

And I've had patients that have had an overall improved quality of life on all of these types of medications. It may not be the full, complete response cure that we as physicians want to see, but they're happy with the result and they're able to get back into their daily life, spend time with their family, do all the things that they want to do.

Dr Todd Schlesinger: And that brings up an important point, because the impact on the family can be very large. We think about the patient, but do we think about the family? And there's been some studies that show the improvement in the impact on the people that surround the patient as well, so very, very important, and important to make about quality of life as well.

So I think we've covered the tumor response, the neoadjuvant, the cemiplimab, but of course there's been recent data that's been published showing that using cemiplimab in the neoadjuvant setting can help improve responses. So that's something that everyone should look at, the recent article in Lancet in 2023. We're now looking at a waterfall plot, just taking a look at the response, and what I see on this waterfall plot is a lot of green, which is a lot of folks who got complete responses, so that's good. So urging everybody to take a look at that data. Any further thoughts on what you would do with this paper?

Dr Aaron Farberg: It's just fantastic to see for these patients.

Dr Harrison Nguyen: I was impressed with the complete pathologic clearance. And the way they structured the study, they had an independent review of the pathologists who were not investigators, and they needed to arbitrate only 10 cases, but the rest were able to demonstrate true pathologic clearance. I think that's very powerful.

Dr Todd Schlesinger: Okay, and then adverse events during the study period, I think, were very consistent with what we'd expect with PD-1 inhibitor therapy. And then the big conclusion of the study was neoadjuvant cemiplimab was associated with a pathological complete response and 51% of those patients with stage 2, 3, or 4 non-metastatic cutaneous squamous cell carcinoma. So that was the conclusion of the study, I think we're all utilizing that in our practices as well.

All right, so any further thoughts on – this is asking us about our thoughts on the efficacy and the outcome. So how does that impact your treatment decisions knowing what you know from this study, generally?

Dr Harrison Nguyen: It's another tool in our tool belt. We integrate patient preferences and other factors and know that this is something that we can and should reach for when appropriate for patients.

Dr Aaron Farberg: Yeah, again, I would just highlight, a 50% efficacy here is actually very good, all things considered. And looking at the patient as a whole is always very important.

Okay, so I think the last theme that we have here is the clinical challenges. So what are the unmet needs in the management of these patients? What are the unmet needs? Anything in the future do you think about? What can we do better? We're doing all we can right now, right? (laughing)

Dr Mark Kaufmann: I think it's to think about the whole patient. And I think it's going to take a little bit of a paradigm shift to think about neoadjuvant therapy in more cases as a potential option to treat the whole patient.