Penn Medicine and the Abramson Cancer Center’s Tara Miller Melanoma Center present a case-based discussion led by a multidisciplinary team of melanoma and cutaneous oncology experts from medical oncology, surgery, dermatology and radiation oncology. The course will review three complex cutaneous oncology cases, discuss workflows, collaborative decision-making processes and the team’s coordinated approach to patient care. It will provide insight into potential treatment options for advanced melanoma, squamous cell carcinoma and Merkel cell carcinoma.
Good evening everybody, we are pleased to welcome you to our continuing medical education event this evening. A multidisciplinary approach to the management of melanoma and cutaneous carcinoma. We have a wonderful Panelist of speakers this evening across our penn medicine system. Um and we'll be introducing each of our speakers um as they come up to present, we have three cases um to present this evening including melanoma, squamous cell carcinoma and merkel cell carcinoma. Um Just as a reminder, this is the course, overview and objectives that you can take a look at and um in order to obtain credits within a week after the meeting, you will receive an email from the Penn CMi department with instructions on how to complete the evaluation and claim your credit and will remind you of this at the end as well. So my name is Shanti seven drin. I'm a medical oncologist um at Penn Lancaster. I'm joined today with Dr. Mira and Dr. Mitchell. And we're gonna be talking about um a pen system, collaboration on a high risk cutaneous melanoma. So this is a case of a patient that I saw at penn Lancaster, it's a 32 year old woman who presented with a new mole in the left supercar vehicular and chest region. In March of 2022. While she was on maternity leave around May, it rapidly started to grow. Um she was seen by dermatology and had a biopsy um and she actually had a rapid regrowth after that biopsy as well, just as background. She had fair skin sunburns as a child. Uh played a lot of outdoor sports. Uh no regular tanning bed use and she did say that she used sunscreen regularly. She had no family history of cancer. An evaluation of the biopsy, she was found to have malignant melanoma and modular type, but the Breslow depth of at least 2.6 millimeters clark level four tills were absent and ulceration was absent. Um The main topic rate was 20 and she had no well developed radial growth phase on the biopsy. So a metastatic melanoma to the site could not be completely excluded. And there was a positive deep and peripheral margin with this biopsy. So I obtained staging scans based on not being able to rule out metastatic melanoma. She had a ct chest, neck, chest, abdomen and pelvis with contrast. And there was no evidence of metastatic disease. We staged her clinical stage at a to a um and based on this, I referred her to dr Meera at penn philadelphia for surgical evaluation. So I'd like to introduce dR Meera, who will be talking about the surgical aspects of this case. Next Thanks so much sean. Good evening everyone. So I'm gonna be talking about the surgical aspects of this case and based on the extensive preoperative work of the doctor scheppingen did. We're pretty confident that we're dealing with the primary melanoma at the time of my initial evaluation of the patient, she had a rapid regrowth of the primary lesion and due to the location of the melanoma which was localized to the super particular region, I was concerned that this patient would have drainage, the level five cervical lymph node contents. And so while the surgery itself is pretty straightforward where the patient would require a wide excision and center of the biopsy, the interesting thing about this case that I want to highlight was how we performed the sentinel node biopsy. A quick comment on the wide excision. The margins that we have tried to obtain for wide excision has largely been established from large randomized controlled trials for any melanoma greater than two millimeters in thickness. We often will recommend a two centimeter clinical margin which this patient has had as far as the center of the biopsy is concerned any melanoma that is greater than 20.8 millimeters. We will often recommend the sentinel perform. And so what is the procedure really? It's a million invasive staging procedure. Were able to identify or rule out the development of micro metastatic disease. And the conventional way we do that is through plain Lindros integrity where we use a radio label column and known as technician 99 where we inject it into the primary site and see where it drains. Now based on this location. I was anticipating a level five cervical lymph node basin drainage and you can see on the plain little integrity images on the right that the dark, dark, dark, dark dot represents the primary injection site and there are a couple of discreet circles around it that reflect possible lymph nodes. Now this is just one dimensional so it's hard to discern where it truly is draining too. But I was expecting it to be within the level five cervical contents. Now there's been emerging evidence and utilization of a different type of imaging study called spect cT scan which provides additional level of detail that can be conserved to augment your early standard windows integrity images. And so we move to the next slide. This this highlights this patient's drainage and how the spec C. T. Was able to identify an unanticipated drainage pattern for this particular patient. So what aspects et does is that it provides an atomic correlation with plain our images. So it infuses the nuclear medicine study with our standard CT scans so that on the bottom left of the screen is the injection site. And you see a bright signal there all. I was gonna expect to see some lymph nodes just posted or deep to that. But in fact what she drained too was a post here neck in transit central node seen in the middle of the screen and additionally a left axillary central lymph nodes. So completely unanticipated drainage. So again based on this imaging and made our subsequent operation much easier in terms of identifying the drainage basin from her primary sites. The next slide please. So she underwent a wide excision with two centimeter radio margins along with sentimental biopsy of both the left post your neck? Central note along with the left. Actually, central note the final pathology demonstrated in melanoma measuring up to 4.5 millimeters. However her margins were widely negative and both central symptoms that we identified were negative for metastatic disease. But given the residual disease present, she unfortunately was upstaged to a final pathologic stage to be without him returning back to shanti to continue the presentation. Thanks Thanks john So when we think about this case and the way that we um on our melanoma team collaborate across the pen system. You know many patients including at your home institutions are able to receive excellent surgical pathology, medical oncology, radiation oncology care close to home. And that was the same at Penn lancaster. But there are some patients that may benefit from close collaboration with our partners at penn philadelphia and so who may benefit um from this collaboration. And so examples of this include complex surgical cases that would benefit from a melanoma focused surgical oncologist like dr mira clinical trial candidates. So we have a robust portfolio of trials in this space. Neo adjuvant melanoma trials. Stage four treatment trials in melanoma and merkel cell cancer trials. Uh There are patients who are candidates for most surgery for special sites for example in the head and neck. And we have a very robust program and um who need advanced reconstructive surgery and then patients who may need consultation in the pigmented lesion clinic. So why did we refer this patient? So this patient was discussed in our pen um system wide melanoma tumor board which is a great way to bring complex cases um and get a lot of opinions at once. And I encourage all of you if you have a case that you would like to get these expert opinions on, um you're able to present the case that our pen melanoma tumor board that meets virtually every Wednesday at noon and to place a case. You can I put the contact information of Aaron flowers on there. Um and that information will be available at the end of the presentation as well. Um and then another way to get your patients um seen kind of seamlessly is collaboration with molly Cassidy who is our melanoma nurse navigator and is able to get patients in very quickly and seamlessly um to see our expert team. So this patient was referred after the discussion in tumor born. She had she had a rapidly growing melanoma in the neck region and we discussed where this lymph node assessment can be difficult. Um It was unclear for the primary lesion was metastatic from another site. It was a complex surgical case and we had discussed at tumor board that if the patient's melanoma was a higher stage after surgery which in this case it was um staged at A to B. There would be consideration for adjuvant immunotherapy and that is something that she was able to receive and is currently undergoing um with myself close to home in lancaster and dr Mitchell who is a medical oncologist and penn philadelphia is gonna walk us through how we assess our melanoma patients. Um for a german immunotherapy. What are the pros and cons and how do we have that risk benefit discussion? So dr Mitchell take it away. Thank you. Doctor said Fondren and dr mira for walking us through that interesting case and collaboration. Um I'll talk about adjuvant therapy for stage two and three melanoma to give an update on the latest data and practice. Currently there are three adjuvant therapy options that are in use for melanoma including Deborah mutant. Stage three melanoma. NovoLOG man for stage three melanoma and pemberley is a map for stage three melanoma and which has also been recently improved for stage two melanoma and I'll show you some of the data on the next slide. Um All three of these regimens have been shown in randomized Phase three controlled trials to improve recurrence free survival meaning that at um you know analysis at 3 to 5 year follow up which is about the length of time we have since these studies were conducted. Um There remains a significant reduction in the rate of recurrence in patients treated with either P. D. One block or um or have been traumatic. However there hasn't been any confirmation of survival advantage for adjuvant therapy in melanoma. So there's no clear data that tells us that it's better to treat everyone in the adjuvant setting versus a watch and wait approach and treating patients when they develop Stage four disease. Though there's a clear recurrence free survival advantage for any of these regimens. So because there's a certainly a clinical benefit of reducing recurrence despite no um survival advantage that's been clear in the in the era of currently active and effective therapies for Stage four disease. It's very important to start the conversation with these high risk Stage two and stage three patients with an individualized risk assessment of what is the likelihood that this patient that you're meeting with is going to have a recurrence of melanoma. And so whether it's stage two B. Two C. Or stage three, all of which there are FDA approved options for adjuvant therapy, we need to start by going over the risk of recurrence and you can see here by a. J. C. C. Eight criteria um that the 10 year melanoma specific survival is actually quite excellent for stage three A patient's. And so you know in these patients want it's very reasonable to pursue observation with history and physical exams and cross sectional imaging rather than an adjuvant therapy which is the case for really any stage two and three patients but how the patient considers the risk and benefit in their decision making really starts with what their actual risk of recurrences at the time of their initial meeting with us. And of course for those patients with Stage three C. And D. Melanoma in which we're telling them that their risk of recurrence is as high as 50 to 70% in the next 1 to 3 years. They may view it as you know, a more reasonable decision to pursue actual therapy despite the risks associated with it. So more recently I showed you the data for the stage three benefit in recurrence free survival for therapy. More recently, Pemberley was also approved for Stage two B and C melanoma based on a randomized phase three study of 976 patients with the primary endpoint recurrence free survival. But now we also have more recent data presented at the asco meeting in june of 2022 regarding um distant metastases free survival. And again there's been no survival advantage that's been demonstrated to date from this. Uh use of temporal is a map in stage two or three. So here are the most updated data from the keynote 716 that showed the benefit in stage 32, B and C. And you can see at 24 months there's certainly a statistically significant reduction in the Risk of recurrence on the order of about 8% there where you can see in patients receiving placebo there were 28% of patients had recurrence events versus 19% in those receiving embolism. And then here this was presented for the first time over the summer. The distant metastasis free survival, which may be a more practical or important way to think about it for patients in the discussion that at 24 months or at two years there was a 6% absolute reduction in the rate of appearance of distant metastatic disease. So again, there was a rate of 19% versus Approximately 13% or 6% difference in patients treated with embolism map compared to placebo in the appearance of distant metastases. Again, there is a high rate of response, durable response and durable rate rate of cr in stage four patients as well. So we don't have long term follow up about a survival advantage of treating these patients. Um, compared to treating at the time of stage four. So how do we weigh these benefits with the possible risk and the decision of who needs adjuvant therapy? So, as I mentioned, it starts with the risk of cancer recurrence and to be clear sentinel lymph node biopsy is critical for this risk assessment. Um, I think there's some, you know, confusion in the melanoma community recently after the approval for Stage two about sentinel lymph node biopsy because patients who are already clinical stage to be or see by their biopsy alone are technically eligible for adjuvant therapy. However, that's incomplete data without the surgical staging that comes with a sentinel lymph node biopsy because these patients can be upstaged to stage three C. Disease and have a much higher risk of recurrence. And there is not a default to treat these patients. So the actual risk of recurrence is a key piece of the decision To treat or to observe. So what on the other side are the risk? So certainly the very common risk of permanent hypothyroidism. 20-25% of patients, the risk of rash, itching, joint pains and then there's the permanent adverse events. Um and then the risk of death which is small but not negligible that there can be death due to autoimmune toxicity including due to pneumonitis or myocarditis or really any organ failure including um complete red cell a play, asia neurologic catastrophes as well. Um That results in permanent toxicity as well as the time and cost spent traveling to visits. So we need to weigh the potentially severe side effects in that can happen with the risk of recurrence and the potential benefit of improving cancer free recurrence free survival. So to summarize here it certainly reduces the risk of recurrence in two B and C. And three and two C. Melanoma. But we don't have long term data or confirmed survival benefit and therefore close observation alone remains an equally reasonable option for stage two B and three. And it really comes down to a shared decision making between the medical oncologist and the patient. So at penn our practices to refer all patients with stage to be and above to medical oncology to have this shared decision making in this complex conversation about the options. And also for us to continue to monitor these patients with cross sectional imaging every six months for stage two B. And above patients um including ultrasound of the nodal bed. In patients with stage three melanoma who have not undergone a completion lymph node dissection as part of the standard of care after MSL T two showed no improved survival with completion lymph node dissection. And of course these patients still need to continue their routine skin screening and parallel with their oncology follow up for five years. The lifelong need for dermatology skin screening given that they have at least 5 to 10% risk of additional melanomas during their lifetime as well as um squamous cell and basal cell carcinomas. I think the next is my last slide here. So I'll end by talking about neo adjuvant therapy because there's been some very recent data um that was presented last week at the Esma, the european Society of Medical Oncology meeting 2022. And so it's been established that neo adjuvant therapy or giving um immunotherapy prior to curative intent surgery for stage three clinical respectable disease um has a problem value and that the pathological response at the time of surgery after even just 1 to 3 infusions is prognostic of long term recurrence free survival. Now for the first time we also see that there's a clear increase in improvement in event free survival and recurrence at two years with neo Adjuvant versus Adjuvant therapy in the randomized S. 18 01 clinical trial in which patients received three doses of Pemberley is a map followed by reception and then completed a year of adjuvant therapy or reception and followed a year of adjuvant therapy. Um and there was a, you know, a difference of 49 versus 72% of patients that remained cancer free based on having the advantage of neo adjuvant therapy. So this new this approach offers potentially an opportunity to individualize treatment based on the pathological response at the time of surgery. To either intensify adjuvant therapy if there's less than an optimal pathological response and possibly even in the future to limit surgery or adjuvant therapy or you know, image monitoring these patients. And there's certainly also the potential to gain insight into mechanisms of treatment response and resistance by analyzing the tissue at the time of reception on treatment. And we have state neo human clinical trials ongoing at penn for patients with clinical stage two or stage three clinical respectable disease. So these patients who are clinical stage two B or two C already by biopsy can be referred for these to any of us for these clinical trials to start with pemberley Samad before going on to surgery and then to receive a job in therapy. So to summarize aspirin therapy can reduce recurrence in patients with high risk disease but it requires a complex, shared decision making of risks and benefits with the medical oncologist and close follow up alone remains an equally reasonable option. Um pathological risk. Neo adjuvant therapy are certainly prognostic of decreased recurrence and the S. A. T. No one recent results may further define the role of new agent therapy for stage three clinical respectable disease. But at this point it remains an investigational approach reserved for use in clinical trials. Um So with that I'll move on to our second case and I'll introduce dr Joanna walker, one of our terminal logic surgeons to walk us through the next case of squamous cell carcinoma. Thank you Dr Mitchell. So um myself and Karthik Rajasekaran, I'm in dermatology. Most surgery and dr Rajasekaran is in head and neck surgery. We have a case that we wanted to share with you. Um First we'll go through a little bit of overview and then we'll talk about the management of cutaneous squamous cell carcinoma for the primary tumor regional disease as well as adjuvant treatment. So just to review cutaneous SCC is the second most common skin cancer. It's extraordinarily common. The incidents continues to increase and for invasive SCC there's a 3 to 5% risk of metastasis. This actually leads to we estimate about 10,000 deaths per year in the United States which is fairly similar to the deaths caused by melanoma and our patients that are immuno suppressed um or have solid organ transplants are at particularly high risk for bad outcomes. It's important to be aware of multiple clinical histological and demographic prognostic factors so that we can better sort of narrow down which patient or which tumor is the one that's going to be higher risk for metastasis. So we'll present our case. We have a 65 year old gentleman. He has a past history of recalcitrant multiple myeloma and he's had several karate site carcinomas which is the inclusive term for basal and squamous cell skin cancer. He presents with a new scabbing area on the right cheek along with sensations of a deep itch and a tenderness that radiates along the brow in the in the distribution of the zygomatic temporal um nerve. He had had most surgery done in the same area eight months prior to treat a cutaneous squamous cell carcinoma. His medical history is pertinent for his multiple myeloma and that he had relapsed in recalcitrant disease status. Post multi multiple treatments including autologous stem cell transplant. He had had multiple rounds of palliative radiation including to the c spine and currently he was on treatment with um Carpizo cyclophosphamide and dexamethasone zone. So at this point we take a step back and we think through what information we have based on his clinical presentation. And for our staging for cutaneous squamous cell carcinoma according to the A. J. C. C. Staging system. His tumor is greater than two centimeters in diameter. So he'd be a T. Two stage according to the Brigham and Women's Hospital. Again based on diameter he's A T. Two. A. Although you could argue to use the clinical signs of peri neural invasion that would bump him up to a. T. To be. However we know that the staging systems for cutaneous squamous cell carcinoma are incomplete and don't always detect the individuals that are at higher risk. And so the other issue with it is that most of the factors included in these staging systems are histological factors. So usually i on your first assessment of a patient based on the biopsy you don't have a full evaluation of their histological prognostic features. So based on some of the clinical features that we know in this case including him being on systemic immuno suppression. This being a recurrent tumor having signs of paranormal invasion. And the fact that this tumor on palpitation was bound down and felt deep. Um although not fixed to bone. We had a high suspicion for this being an aggressive tumor and at risk for regional metastasis. So at this point we're thinking we need to do further work up and involved some of our colleagues and so we reach out to our head and neck colleague. And at this point um dr Rajasekaran is going to take us through the next steps. Thank you. Dr walker. This is probably the best part of my job receiving a phone call from experts in our dermatology department. You know as dr walker mentioned um This is a high risk patient, his immuno suppressed recurrent tumor. There's also concerns for peri neural invasion. So uh and a lot of our patients are not from this area. So we try to think about next steps um and try to um coordinate all the appointments such that it's convenient for the patient as well as expedite treatment. So the first major major thing that we need to think about is what type of imaging to order. Um There's several types of imaging cat scan. M. R. I. Ultrasound that all of them have their unique advantages and disadvantages in this particular case with their concerns for paranormal invasion along the zygomatic branch and M. R. I. Would be more useful. Um One can make the argument that a cat scan could also be useful to tell us if there's deep involvement. But uh in as far as I'm concerned if it's deep I would respect part of the maxillary bone and a cat scan would not be as helpful. So we elected for an M. R. I. Um I apologize my daughters on the screen. Um And then the next thing we think about is the need for an F. And a. Um if based on the scan. So um so these are things that we discuss over the phone during dr walker's initial visit when the patient initially visited. Dr walker. And the next thing we talk about is um how do we coordinate appointments? Um So oftentimes we can do the most surgery and dr walking can do the reconstruction at the same time. And then the patients sent to me to address the local regional disease. Other times we dr walker will do the most surgery and then send the patient to me to address the local regional disease and do the reconstruction. Um that decisions made based on where the tumor is located, how sick the patient is um etcetera. Next site please. So for this particular case what we decided to do was we got the M. R. I. And then the patient will see me back after the M. R. I. And then dr walker felt that she could um she would be able to do both the most and the reconstruction at the same time. And um and that because we were primarily worried about uh prodded and neck disease that this would be sufficiently low enough that we could stagger the uh that I could do the surgery after she did both the most um and the reconstruction next slide so we got the M. R. I. Um and this is what it showed on the bottom left of the screen. In the tail of the prodded there was a nine millimeter enhancing nodule um and likely to be uh thought it was thought to be an interpreted uh met um there was also an incidental finding on the left side of the patient in the in the man and the angle of the mandible. Um That was known that was known to be from his prior multiple myeloma. Um Since there are no other lymph nodes. Um the question again becomes, do we need to do a needle biopsy to confirm the enterprise? Did uh met. That. That is a question we we can consider but in this case that he he has such such high risk factors. I don't think it would have changed our management. So we elected not to do a needle biopsy next slide. So at this point I'd hand it back to dr walker who will take us through the most surgery. Alright. So we bring the patient in and we know we have a few principles um regarding the treatment of these high risk tumors and and treating it with most micro graphic surgery. And what we want to really um utilizes our ability for the complete margin assessment microscopically so that we can really track the tumor out and clear the margins. The other thing that's important for us to do is to evaluate the tumor itself or what we call the D bulk so that we can get additional information about the tumor about what we're looking for and so that we can complete the staging criteria. So we usually will um as you can see in the photo here on the right. We usually will take a map drawing of the area we're removing. Um and section out bread loaf slices of the tumor and then assess that on frozen section slides as well as sending samples out for permanent sections to um document the staging criteria. Next the other thing that we do is we use sido keratin, immuno hist o chemistry stains to help us track the tumor. And so you can see on the left, will usually have two sets of slides for each slice. And that is the H. And E. As well as the immuno stains. And as you can you see on the two images on the right and this is this patient's images. It really highlights with the immuno stains on the right where you see the brown cell surrounding that nerve. It really brings forward the peri neural invasion and other features of the tumor. And and so this is the look at this patient's tumor. Um We can see on the right the brown or the tumor cells. We can see that it's deeply infiltrating as you get lower down. It has single cell spread. Um It was poorly differentiated and again at the very bottom right, there was perry neural invasion. So it just confirms our clinical suspicion that this is a very high risk tumor. Then the next step is to do the most layer. And again we have this mapped out and inked in a way where we can very precisely control um when looking under the microscope that we know what we're looking at and where. So that if we have two more left we can go back and precisely remove it next. And again. This is an example where the psycho carton immune estates were so incredibly helpful and that you can see in these images that this tumor had just small groups of one or two cells. Um And it was there was some residual tumor cells on our layer um that was within skeletal muscle. So we were able to map that out and um fully clear the tumor with a second stage. So here's our clinical pre op photo our defect photo and at this point we placed integra matrix um and put a bandage for the patient. And then he went home and the next day I went in to see dr Rajasekaran. Thank you dr walker. So at this point the primary was addressed. So we go to the local regional disease. Um Just to recap he had on his M. R. I. To findings one in the left mandible that was related to his multiple myeloma. Not concerning for our tumor. I mean not concerning for our surgery. And the main thing was that he had this right millimeter nine millimeter nodule in the tail of the prodded consistent with enterprise and nodal metastasis. So next side please. So in terms of guidelines, the N. C. C. N. Makes it very clear in terms of what needs to be done for this. So this gentleman had a prodded node uh involved and the recommendations excision of the primary tumor um Which dr walker did a superficial prodded ectomy and skeletal neck indication, neck dissection as indicated. Um I'm usually pretty aggressive on these cases because I would argue that prodded ectomy is probably more challenging part of the case adding on an extra section doesn't really add much morbidity. Um so I do a pretty comprehensive neck dissection and then in terms of the the management after that there's a few different options. So there's only one positive node less than or equal to three cm. And no ec we either recommend radiation or observation. There's two or greater positive nodes or one node greater than three centimeters. Again with no ec. Then we'd recommend radiation. Any node with E. C. E. Or extra capsule extension. Um radiation is recommended and often we would consider concurrent chemotherapy and lastly if the note is incompletely excised. Then we would recommend radiation and again consideration of uh systemic therapy. Next slide So this unfortunately is not the patient. Um This is not our patient but you know I felt like dr walker had very pretty pictures so I try to provide some pretty pictures to show I can do something. Um So this is just a standard incision that we would do and I wanted to highlight that um the the way we designed the incision. we have to be thoughtful. I didn't want to I don't usually like to do in the direction that would affect dr walker's reconstruction. So I designed this is a standard incision and the picture on the right kind of demonstrates how aggressively are. You can see like you can see um those little white branches that's the facial nerve, all branches of the lower division, resected the entire prodded and then complete neck dissection through an incision like that. Next slide. And generally speaking this is how they look from just a prodded uh incision. So they heal pretty well. Next slide. So in terms of his pathology he only had one note that was positive that was the interpreted lymph node. The product gland was considered to be benign and the remaining 17 notes from the neck dissection that were removed. Also benign. And as we knew from the M. R. I. That lymph node was less than a centimeter in size which was also less than a centimeter in size. Uh pathologically. Next slide. Uh So at this point dr walker will go over um the management of this patient following the surgery. Thank you Karthik. Your pictures are beautiful and your surgeries are even better. So um at this point typically when we have identified and treated a high risk cell carcinoma. Um We'll want to circle back around and have a multidisciplinary discussion, bring it to tumor board. Review N. C. C. And guidelines to see if this patient would benefit from adjuvant therapy. And the most common adjuvant therapy is radiation treatment. And in stage three disease of um cutaneous squamous cell carcinoma. That does look to improve local regional control. And as you saw with the N. C. C. N. Guidelines particularly for a higher burden of disease and the nodes and extra capital er extension. It's recommended fortunately in our case our patient was an in one and um because he was needing to get back on his chemotherapy for multiple myeloma we actually decided to um have close surveillance of him so he did not get it. But we're often discussing this. And then the other thing that we discussed is whether um to do chemo chemo radiation. There was one randomized controlled trial just recently that's been helpful in guiding us that showed that the addition of carbon Platten with adjuvant chemo radiation did not improve outcomes overachievement radiation alone. Um But as you know there are other systemic therapies that are approved for um cutaneous squamous cell carcinoma. So this may involve bringing in our medical oncologist to discuss um what to do with the patient which brings me to my second point regarding the high risk cutaneous squamous cell carcinomas pen. We have a randomized controlled trial um With the addition of a simple map used in the adjuvant setting. And so this is used for high risk squamous cell carcinoma that's recurrent and locally advanced or that is regionally metastatic. And the trial follows the treatment of surgery and adjuvant radiation. Um Again in the case of our patient he didn't qualify for the trial because of his active management of multiple myeloma. But these are things we're able to consider. So you can see here um our patient um pre op inter op and post op he's doing well needing a few um staged reconstructions but he's doing great. He has no evidence of disease at four months and we're continuing to follow him really closely. Nice. So we hope that this case um highlights that it's important to identify high risk cutaneous squamous cell carcinoma features if possible clinical features. And up front so that you can order appropriate imaging and plan pre operatively. And that often includes an interdisciplinary surgical team and we try our best to coordinate our schedules and provide cohesive treatment to the patient um for these tumors. Most micro graphic surgery with immuno hist o chemistry improves our ability to detect the tumors at the microscopic level. And in a review of our cases is associated with less than 2% risk of recurrence in high risk cutaneous squamous cell carcinoma. In these cases. We often will be considering adjuvant treatment with radiation therapy and clinical trials. And I think I hope that it highlights that really were able to um maximize each of our individual strengths by working together in order to provide comprehensive care to our patients. And now I'd like to introduce john mira are oncological surgeon to present our final case of the evening. Thanks so much, dr walker. Good evening everyone. So we're gonna change gears a little bit. We're gonna be talking about another cutaneous malignancy that has been gaining a lot of our a lot of attention and rightfully so. And that's Merkel cell carcinoma. And joining me this evening are a couple of my close colleagues dr Emily chew dramatic pathologist within the department of dermatology along with dr nick lukins radiation oncologist here at Penn and just to note he also sits on the N. C. C. N. Panel for Merkel cell carcinoma. So a great resource to have this evening next slide please. So I've selected this case because I think it highlights the importance of a multidisciplinary effort when treating patients with Merkel cell carcinoma regardless of stage at the time of presentation. Um and so to go through that I'm just gonna start off by by this case presentation. So this was an 85 year old man who had a remote history of chronic lymphocytic leukemia that probably manifested with cutaneous lesions. And he ultimately received radiation therapy to the region which was really his upper back. But several decades later he presented to my clinic with a rapidly enlarging right upper back mass. His past medical history, family history as well as social history as seen below next slide please. But on examination you can see here on the on the picture on the right that there was a roughly three centimeter Aref feminist mass. But when you palpate it, there was significant subcutaneous extension that extended well beyond what you can see at the skin service. Additionally had some tattoo markings just flat to the legion itself that reflected his primary radiation field from his CLL treatment. And on his lymph node examination, I was not able to appreciate any lymph lymphatic apathy. So at this point he had clinically localized disease. So I was subsequently punch biopsy this and dr chu will be reviewing his pathology. Thanks john we're just gonna go to the next slide which shows a portion of the punch biopsy specimen. And here you can see that there are sheets of hyper chromatic cells. And if we go to the next slide, we can see the cells that higher power here. And you can see that these are composed of again, small round blue tumor cells. The individual cells have a high nuclear cytoplasmic ratio. Uh there is an open promoting pattern which is sometimes described as a salt and pepper pattern. Um and then if we go next, you can see that the arrows point out some easily identifiable by topic figures and then we'll go to the next slide and so some additional immune. His chemical work up was performed. And this is the site of care 10 20 stain which shows positivity of the tumor cells and a pair of nuclear dot pattern which is typical for purple cell carcinoma. Great thanks so much Emily. So with the diagnosis that we had at hand was Merkel cell carcinoma. So if this was melanoma, then the next step for this patient would have been a wide excision and a central lymph node biopsy. However, what we've learned in Merkel cell carcinoma is that there's been some emerging evidence supporting the role of preoperative imaging. So if we reference it to melanoma, we know that in less than a percent of patients preoperative imaging ultimately change our clinical management. However, in Merkel cell where we know there's an appreciable risk for lymph lymph nodes spread even among the smallest, even along the smallest lesions. There's been a lot of interest in performing upfront preoperative imaging in the form of a pet ct. To determine if patients would ultimately be upstage, which will change management. So for this particular patient, this is his pet ct we see here on the screen left his primary site that remains pet avid on his right upper back. However, when we looked at the right axillary lymph node basin, which is his anticipated drainage basin of that region of his body, we see a couple of abnormal lymph nodes, one of which is about two centimeters in size house pet that was subsequently biopsy and biopsy proven to be metastatic merkel cell carcinoma. Next slide please. So to highlight the importance of preoperative imaging. we see I'm including this particular study here that was published last year in Jama dermatology Where this group published their series of a large series of roughly 580 patients with clinically local regional disease. But I want you to turn your attention to the left side of this diagram here when they looked at the specific subgroup of patients that had no at an open these. So these are clinically localized Merkel cell patients who all underwent clinical or preoperative imaging in the form of a pet roughly 12 12% of patients or one in eight were clinically upstaged to stage three or stage four given the findings that were on pet scans. So changing management and so I think there's a lot of good data supporting the role of upfront imaging or preoperative imaging for Merkel cell. Unlike a non Oma. And if we refer to current N. C. C. And guidelines they currently encourage the use of preoperative imaging for any person presenting with a newly clinically localized merkel cell carcinoma. Next line so with respect to his surgery. Again, if we didn't have that piece of information that he would have undergone a wide excision and sentinel lymph node biopsy. Now, regardless of the Merkel cell size we often will recommend sentinel lymph node biopsy If a patient can undergo general anesthesia for this patient since he now had clinical stage three disease. The recommendation was to perform a wide excision with a right axillary lymph node dissection. A quick comment on margins for merkel cell carcinoma, we don't have good level one evidence of what the optimal margin is. But from what we can glean from the available data that we do have, it appears that a 1 to 2 centimeter margin is adequate as long as we can obtain a pathologically negative margin. But there's a caveat here being that this tumor is extremely radio sensitive and therefore many of these patients will receive adjuvant radiation therapy, which dr Lukens will discuss in the subsequent slides. However, as we know, these tumors can get quite large and so obtaining a widely negative margin. Even obtaining a one centimeter clinical margin can sometimes result in a large defect that would result in the need for skin grafting. So there's been some new interest in performing complete tumor extrication with the ability for just prime closure. If we anticipate radiation therapy to be delivered post operatively to spare patients skin graft and the ability to go on to radiation in a more timely fashion for this particular patient. He had enough laxity and the lateral aspects of his of his primary site that I was able to obtain a one centimeter clinical margin. And I also performed a write extra lymph node dissection at the same time. His final pathology is seen below. So in total the mass measured about 4.4 cm in greatest dimension. All he had some focal paranoia in Beijing present and all margins were negative with respect to the right axillary contents. 23 limb films were identified to positive for merkel cell carcinoma. And extra capsule extension was noted. Uh interestingly all his lymph nodes were involving a Cll so you can see four weeks post op. Uh this patient is healed very nicely and based on this pathology we did discuss this case at our tumor board and there was some strong recommendation for him to consider radiation therapy which we refer. Which who I refer to. Nick Lukens two to evaluate. So I just want to introduce dr Lukens. Next we'll be going over radiation for american. Hi, good evening. Thanks so much for having me john. And for the introduction. So um when it comes when it comes to indications for radiation therapy for merkel cell carcinoma. As we all know these 10 these have a high rate of local recurrence. Um regional recurrence and also just in metastatic dissemination. Um We consider the need to radiate the primary site and the regional nodal basin separately. Um general um reasons to consider radiation would be the size of the tumor. So in this case with the tumor um that was um 4.4 centimeters. We would definitely consider the use of agent radiation to produce the risk of a local recurrence. Um The other um reasons for considering radiation would be lymph vascular invasion pairing neural invasion, closer positive margins or um immuno suppression when it comes to whether we need to radiate the regional nodal basin generally um In patients who have had a positive sentinel lymph um biopsy without a completion dissection. Because these tumor cells are relatively radio sensitive. We can get away with radiating, radiating the excel without necessarily having to do a completion nodal dissection. In certain cases if there's more than one note that's positive and if there's Ec then generally we're going to be treating with post op radiation to the regional nodal basin. Next slide please. Um When it comes to general principles. Adjuvant radiation for merkel cell carcinoma. Um Generally we're going to treat with wide margins. That's because these can recur pretty far from the primary tumor site. Um We like to start as soon as possible as dr mira mentioned once the wound has healed. Um In general for most cancers, we try to start within about six weeks of um surgery. In these cases where we often want to start even within 4 to 5 weeks of when they've had surgery. And as Dr Amir mentioned, this is where it's really important to discuss with the surgeons. Um as far as how the wound is gonna be closed because you want to minimize the time to starting radiation and we'll talk a little bit more about margin status and radiation in one second. As was mentioned, these merkel cells are very radio sensitive. So low doses will often suffice to get the job done. The standard of care historically has been um for the primary site we typically give about 50 gray over five weeks. That's 25 fractions. Um There's some data specifically for head and neck merkel cells in elderly patients that you can give eight grade times one fraction small retrospective study showing a high rate of local control in patients who have indications for radiation. Um So it's something where we will sometimes consider short of course radiation. Um And there is some retrospective data to support as short as two or three week long radiation courses. Um It's worth noting that there is some data that um if you follow the N. C. C. N. Guidelines um as far as when to give radiation that is associated with an improvement in overall survival. So it's worth um you know considering radiation for these patients even who appear to have relatively favorable you know pathologies, relatively small tumors that are no negative. We still consider radiation for those. Um Next slide please. Um So this is this is the advent radiation plan for this particular patient. So he he was treated with I. M. R. T. Which is really the standard of care here uh 50 gray to the back to to the primary site. And here we wired up the incision and treated with a relatively wide margin and then we also treated the right Exelon given the presence of multiple 1000 nodes as well as ec. Um And here we gave 54 grade to the right Excellent. Um Next slide please. Um This is a study that dr Amira was referencing here. Um This is out of the university of Washington. It was published in the J. D. Um last year um with reference to um need for wide margins in patients where you know that there's a high likelihood of needing um radiation in the postoperative setting. So in general we do like to get wide margins where the one centimeters. However this study suggested that um it may be okay to have slightly narrower margins with the primary closure in those patients that um will be treated with postoperative radiations here. So as you can see in the figure on the right those patients who had radiation um generally there wasn't a significant difference in terms of the local control rate based upon the margin. Um Next slide please. So I'll hand it back over to dr muir now to talk about systemic therapies for merkel cell carcinoma. Great thanks so much nick feels great you know so despite our best efforts at delivering you know um radiation as well as providing negative margins on our surgical receptions, the challenge we face with respectable Merkel cells. So stages one through three is the high rate of recurrence. So some published series report up to 50% recurrence rates. So there's been a lot of interest in delivering systemic therapy for earlier stage disease. But currently this remains an area that is um that there's just a possibility of, of literature. We have learned over the recent years that noma is an extremely mediagenic tumor. But prior to 2020, chemotherapy remained the standard of care for advanced as well as metastatic Merkel cell carcinoma. And it was quite effective. It resulted in a high overall response rate of about 55%. But the challenge we faced with chemotherapy is that for many of these patients it was not durable for about 50% of patients. They would have progression following initial response within six months of initiating treatment. Fast forward a few years. And what we learned is that with the delivery and the development of the immune checkpoint blockade and studying it within Merkel cell carcinoma, whether it's delivered in the first line, such as the keynote trial where petrol is a map was investigated or in the second line, the javelin where available was delivered. We see not only high overall response rates that are similar to what we saw in chemotherapy, but these responses were also durable. And so as a result, many of these patients are deriving a survival benefit when compared to historical controls such as chemotherapy. So seeing these really exciting results, there's a lot of interest in seeing whether or not we can deliver immunotherapy to earlier stage respectable merkel cell carcinoma. Next slide please. But unfortunately, as I said earlier, this remains an area of active investigation we have this is a data free zone Instead what we have are multiple active agreement Merkel cell trials that are currently being conducted throughout the country and also in europe. I highlighted the top trial there called the stamp trial which is currently being offered here at Penn. It is a peacock sponsored trial randomized where patients with pathologic 123 B Merkel cell that has been respected most subsequent undergo randomization to either pembroke versus placebo. Many of the primary endpoints are similar among all these trials but they're using a different type of checkpoint blockade in their particular study. But what you can see here is that, you know, it's really important that among that every patient that's treated for Merkel cell carcinoma will be at least considered for clinical trial enrollment given that we need to be able to answer this question. Next slide please. But one thing that we're really excited about here at Penn is that in the next month we will be opening our own investigator initiated neo magic isn't immune checkpoint blockade clinical trial for respectable merkel cell carcinoma. This is U P c c 016 to two and the clinical trials identifiers scene at the bottom right of the screen if in case you want more information about this particular trial. But here's the trial Schema, we hope to accrue about 15 patients over an 18-month period. And patients with clinical stage one through three are eligible for this study, patients will receive approximately one dose of embolism that was subsequent, undergoes surgery three weeks later and following their convalescence. They will undergo an additional year of embolism at, at six week intervals. We have many exciting corollary studies that we have proposed and we will be collecting both blood as well as tumor, both pre and post treatment. So something to be considered for any patients that you see that may be eligible for this study. We will be having this open in later this year. Next slide please. So just to close a couple important points about Merkel cell. I think all cases deserve a multidisciplinary discussion. Um, given that they will likely require not only radiation complex pathology that goes into the initial diagnosis and initially they may require or may be eligible for enrollment on a clinical trial. Additionally, preoperative staging scans appears to be very beneficial. As one in eight patients may be found to have additional disease that would ultimately upstage them and change their management for any patients that have clinically localized Merkel cell that do not have distant disease. On staging scans. The standard of care is a wide excision and sentimental biopsy regardless of the size of the Merkel cell, primary tumor, Given the appreciable risk for regional metastases. Last. Next radiation therapy, as dr Lukens has demonstrated, is very effective in local control following a wide excision and so timely initiation of therapy is critical here and so we can obtain complete tumor extrication by still obtaining a primary closure. I think that is best. We have some really great data supporting the role for checkpoint blockade for Merkel son in the advanced and metastatic setting that is results in durable responses. And hopefully this will translate into our early stage merkel cell patients. And we are currently actively investigating that in both new achievement as well as active, active ongoing human trials that are in the pipeline. And with that I'm gonna stop and we're going to open up the panel to questions Dr Mitchell will be leading the last session. Thank you so much. Thanks dr mira and I'll ask the participants um to continue to enter your questions into the chat function as well. And for the panelists to come back we have some great questions in the chat and I'll start by addressing the first one to dr Lukens. Um what is our institutional practice of adjuvant radiation therapy for stage three melanoma? Um So that's a great question. Um Generally we follow the guidelines say that I laid out previously. So for most stage three patients were going to be considering adjuvant radiotherapy um to the regional nodal based and plus size. The primary site with some notable exceptions if patients have a positive sentinel lymph node and then go on to have a completion dissection that has a one small note positive or um no additional lymph nodes that are positive in that case there's there's data that there's probably no role for radiation to the regional nodal basin in in those cases. Um but generally for stage three patients um with a high burden of nodal metastatic disease, we're going to be treating the regional nodal basin to reduce the risk of our currency. Hope that helps answer question and then I'll address another. Thank you. Dr lipkins. I'll address another one of the questions here we have from a participant. How does metastatic and recurrent treatment change in patients who have already received adjuvant therapy? That's a great question. And one that's more commonly comes up now that patients are routinely getting adjuvant therapy. Um So if a patient has received adjuvant immunotherapy um with NovoLOG membership embolism ab we would usually default to dual checkpoint blockade with and NovoLOG map and these patients for their first line immunotherapy. Um We had recently results published on the dream seek study showing that there's a survival advantage in patients with BRAF mutant melanoma for treating them with immunotherapy before targeted therapies. Our general preferences to start with immunotherapy. Even those who are B raf mutant. However many of those patients in the era of the dream seek were not treated with adjuvant therapy. So in patients who do have a B raft mutation. It's also reasonable to consider B raf and MEK or dual checkpoint blockade, but I would be less likely to use single agent immunotherapy or PD one blockade as the first line if they've recovered after um Adjuvant pd one blockade. Um And then there's another, you know there's another great case question which I can start to answer and then may differ to some of my colleagues, essentially the question from dr jang is a patient who Rikers five years after stage three melanoma who now occurs within an isolated lung metastases 1.7 millimeters centimeters and no other disease. Uh And but they have psoriatic arthritis. How would you treat this patient? Um So I think there's a couple of interesting points here. I think that the five year timeline um is important because sometimes these patients can't have true biologically ah legal metastatic disease. And having an isolated site five years after the primary. I mean after the stage three you feel a little bit hopeful um that this could be oleg a metastatic disease biology. Um And given the story attic arthritis, sometimes we've considered um you know, reserving immunotherapy for if it become more multifocal, certainly psoriatic arthritis or methotrexate are not contraindications to immunotherapy. And we would just treat this patient with observing for toxicity and managing it concurrently. But I would also like dr Lukens to weigh in on the efficacy of S. P. R. T. For isolated metastatic lesions. Thanks So I would say this is sort of an ideal case of where we would consider treatment with S. P. R. T. Which is a focal high dose radiotherapy. Usually over 3 to 5 treatments given over about a week and a half to two weeks. Um When we treat in this fashion sorry there's a very there's a reasonably high rate of local control of the treated lesion For Merkel cell probably than higher higher than 90% if we're giving a dose of about 50 gray and five fractions which would be relatively standard for for an isolated lung metastases. So we usually we enter it into this with open eyes though realizing that um this may be the tip of the iceberg. Again the patient may have to go into you know systemic therapy but perhaps we can delay the time to that happening as long as we're not going to cause excessive toxicity which usually sp R. T. To one lung nodule is pretty well tolerated. Um And you know I have a question that came to mind when we were discussing the Merkel cell case um for dr mira and maybe doctor lukin. So you know given the emphasis that you placed on time to initiation of radiation and um the need to move on quickly to radiation and the radiation sensitivity. What would you suggest dr mira in a patient with um say a slight positive margin of the primary Merkel cell. Do you go back in for re excision of a small positive margin. If the decision is already going to be for adjuvant radiation. how do you manage that patient along with dr Lukens. Yeah, that's that's a really great question. And certainly a challenging scenario. I think as you know, nick or dr Lukens demonstrated in some of this his slides there's some good data now to support that even if you have a microscopically positive margins. So it's a little bit different if you're dealing with a true macroscopic versus microscopic positive margin if you have a microscopic positive margin. So I certainly think that it's not unreasonable to go on and move to radiation. However, if you have a grossly positive margin where you still have residual disease, I think you should take a long look at whether or not you can go back and re respect the clinical residual disease to get even a microscopically positive margin just so that you can clear it as best as possible. But you have to also weigh the risks of the morbidity of re reception. But certainly a challenging case. Yeah, I would just weigh in that. I would say it's somewhat common to see a positive margin in an area where it's challenging to get negative margins. For example the eyelid or around the eye where, you know surgeons naturally don't want to have to do an orbital exoneration. And so we're asked to treat with postoperative radiation and um with a dose of about 60 grade Which is about six weeks worth of radiation and careful planning to spare the eye Um I think it's usually reasonable in those cases as as you said dr mir with a microscopically positive margin. I would favor proceeding with radiation knowing that you're probably gonna have to treat anyway. And with a slightly higher dose we can usually get local control. I think you know, the other scenario that we sometimes run into which is relatively similar is someone who has pretty aggressive disease um surgery and then Rikers during the time between surgery and radiation. Is it worth going back and re respecting prior to radiation? And I think that's one of the more challenging cases and I think um you know we've had cases where we've you know, just going ahead with radiation. We've had cases where we where we've gone back to surgery. I think that's another kind of gray area. I would just throw that out to the rest of the panel and see how they manage that. So we have another interesting question from the participants and we may make this our last question unless the panelists have other questions. Um The question is about the recent data presented at the asthma conference about Neo adjuvant therapy and how do we feel about using Neo Adjuvant Tyvek versus Pem bro? So I guess I'll start by cautioning that I we still consider new adjuvant therapy purely an investigational approach and a pen. We reserve that for our clinical trials of stage three and stage two. Neo adjuvant therapy. I think there's certainly a large growing body of evidence for the use of neo adjuvant checkpoint blockade um At with a short course several clinical trials. And now the large randomized as mo data um support um systemic therapy with PD one blockade or it be an evo in smaller studies um that they have prognostic value of pathological response. And so I think that we have not made it a practice to you use this as a clinical care. Nor have we used back in this fashion. We've reserved back for isolated multifocal skin recurrences in which case it's highly effective and it has a great response rate and can be um you know spare patients the toxicity of systemic therapy and appropriate select patients with injectable lesions. Um But the new agent approach we've reserved for patients with bulky nodal respectable disease. In the setting of a clinical trial though um we may see that this um pen moralism ehsmoh data makes it into the N. C. C. N. Guidelines though. I don't think that there's momentum for some of these other approaches like T beck currently to make it into the N. C. C. N. Guidelines. So I think that we've answered all of the questions from the participants and it's just at 8:11 now. So I want to make sure we have time to show the participants our contact information. Um on the last slide here we have our contact information that you can feel free to reach out to any of the participants at any time regarding um referrals or clinical questions. Or if you'd like to join our tumor board to present a complex or interesting case for for the multidisciplinary feedback. We routinely have all of them members attend from all of the disciplines across penn medicine and we welcome um you know, visiting colleagues to share cases here by emailing any of us or Aaron Flowers are coordinator, which his contact appeared on an earlier slide. Um I think I thank you for your time and interest in R. C. M. E. P. Program tonight. And you will receive a follow up email about claiming your CMI credit um in a week or so from this program. So thank you so much to all of our panelists and to our participants and further wonderful and insightful questions that you posed in our Q. And A session as well. Um and we'll end a few minutes early and have a good evening