Hello, and welcome to the Vulvar Cancer Master Session entitled Modern Management. Thank you so much for joining us today. My name is Dr. Lillian Jian from the Sunnybrook Odette Cancer Center in Toronto, Canada, and I'm co-chair of this session alongside Dr. David Gaffney from the University of Utah in the United States, and Dr. Micah Oonk from the University Medical Center Groningen in the Netherlands. We have a great session planned for today. We have four 10-minute presentations followed by a 10-minute Q&A portion, and we invite you to come up to the microphone with your questions. So I believe we're ready to get started. First, we have Dr. Flora Hinton presenting New FIGO 2021 Staging for Vulvar Cancer. What are the implications for management? Good morning. Good morning, everybody. Good to see all of you live here in beautiful New York City. I want to thank the committee for having me, and today I'm going to tell you something about the new staging of vulvar cancer. I have nothing to disclose. The FIGO committee revised the staging with a goal of simplification. There are now eight subdivisions instead of 11. In stage one and two vulvar cancer, nothing changed. In advanced vulvar cancer, the tumors invading the upper part of the adjacent perineal structure, including bladder and rectal mucosa, are now stage 3a instead of stage 4. Besides the new staging system, the way we measure depth of invasion has changed as well. Furthermore, we subdivided lymph node metastases into macro and micrometastases and isolated tumor cells. Data of more than 12,000 vulvar cancer cases were used. They were prospectively collected between 2010 and 2017. The biggest change was the shift in stage 3 and stage 4 disease. Stage 4 now only contains tumor fixed to the bone, fixed or ulcerated lymph nodes, and or distant metastases. As you can see here, downstaging in advanced stage better reflects prognosis. And here you can see the survival curves. For early stage vulvar cancer, the measurement of the depth of invasion has changed. The new measurement is similar to the method used in cervical cancer. Logically, tumor cells will originate from the nearest reed ridges instead of the most superficial dysplastic crypt or surface epithelium. The figure on the right shows the different methods. Line A illustrates the conventional method, and line B, the alternative new method. Other studies have investigated the alternative method. They showed that this method correlates more with treatment outcome. The tumors downstaged to stage 1A showed overall good prognosis. They furthermore emphasized that the decision for groin surgery should also rely on tumor characteristics. These data show high potential for the alternative methods. However, all data are retrospectively collected. Furthermore, measuring depth of invasion is difficult. Inter-observer agreement is very important because the choice of treatment depends on it. This study showed only moderate agreement between pathologists, with no significant difference between the conventional and alternative methods. The alternative method has shown downstaging with overall good prognosis. However, further prospective studies are needed to validate this alternative method. Lymph node metastases are the most important prognostic factor. This is the main reason why assessment of node involvement is essential in tumors with more than one millimeter invasion. The Groins V study group showed that sentinel node procedure is safe in patients with unifocal tumors smaller than four centimeters and without suspicious lymph nodes. The classification of lymph node metastases in vulvar cancer uses the same definition as in cervical cancer. With macrometastases, micrometastases, and isolated tumor cells. Lymphadenectomy is the advised treatment in case of positive sentinel node. Postoperative morbidity after lymphadenectomy is very high. So, to diminish morbidity, the Groins V2 study investigated adjuvant radiotherapy as alternative treatment. All patients with involved sentinel nodes received inguinofemoral radiotherapy. In 2010, however, the stopping rule was activated due to isolated groin occurrences in 22% of patients with macrometastases. From this point, only patients with micrometastases received adjuvant radiotherapy. In this group, only 1.6% isolated groin occurrences occurred. So, adjuvant radiotherapy in patients with micrometastases in the sentinel node is a safe alternative for lymphadenectomy. With the implementation of the sentinel node procedure, also introduced ultrastaging. With ultrastaging, smaller metastases are detected, including isolated tumor cells. The exact meaning and prognostic value in vulvar cancer is unknown. In 2010, the study group of ONC investigated the risk of non-sentinel node involvement after sentinel node procedure. And they stated that there is no size cutoff for chance of non-sentinel node metastases. In cervical cancer, isolated tumor cells do not seem to alter the prognosis, but these are often young patients in which adjuvant treatment is given. Yesterday, Dr. Mariani held a great presentation on isolated tumor cells in endometrial cancer. And he stated that uterine factors, histology, and biomarkers are very important in deciding adjuvant treatment. We do not know the exact meaning of isolated tumor cells. In breast cancer, they do not seem to alter prognosis, whereas in colon cancer, prognosis is worse. Dr. Taylor will probably elaborate more on the matter, but based on this literature, isolated tumor cells in vulvar cancer should be managed as micrometastases. This is in line with the advice given in the new ESSGO guidelines. So to sum up, the FIGO 2021 staging system better reflects prognosis. The pathologist is your friend. Size does matter in vulvar cancer. We advise that both methods of measurement and depth of invasion should be used in the upcoming years to validate the new methods. Additional groin treatment is recommended for any size metastases. And further international collaboration is necessary to investigate these matters in vulvar cancer more. Thank you very much for your attention. Thank you, Floor. That was a great presentation. Next up, Dr. Mario Letaio will present, can we use endocyanin green for central nodes in vulvar cancer? Practical tips for the surgeon. The floor is yours. All right. Good morning, everybody. And hope you're having a great time in the city. Can we use? The answer is yes. I'm done. I'm going to sit down. All right. So endocyanin green for groin SLN. Obviously, we're all very familiar within, well, some of us are very familiar with endocyanin green because of our use in both endometrial and cervical cancer. So obviously, a natural idea would be, can we use this for the groin SLN mapping procedure? So these are my disclosures. So everyone's aware of the current standard, quote, unquote, for central lymph node mapping of the vulva, which is with the use of technetium-99. There's no slides? They're up here. I need my slides. There we go. There are my disclosures in case you want to see again. So we all are familiar with the standard of methodology for central node mapping, which is the use of technetium-99, whether it's the day before, the day of, whether you do lymphocytogram, whether you do SPECT-CT. It's all over the place, of course. And then during the day of surgery, we use the gamma handheld gamma probe and blue dye. That's kind of what's been done for many years. And that was basically just extrapolated from breast cancer. Really no other science behind it other than that's what the breast cancer folks did. But the issues are that there is some expense to making a radioactive compound. It's not that expensive. But what's more expensive is the imaging that goes along with it, such as our folks love to do SPECT-CT for some reason. So we get a lot of SPECT-CT images. And last I checked, those are not free. There is an inconvenience. If anybody here has been injected in the vulva while you're awake, it's no fun. So there is an inconvenience and discomfort to our patients by doing technetium-99. We do not do that during surgery, although there are folks who talk about intraoperative technetium. We do not do that at our institution. You know, you're trying to hear things with technetium. So it's like trying to find metal under the dirt a little bit when you're looking for coins in the sand. You do have to stop your dissection to put that gamma probe in there. The blue dye basically is really limited, I think. I won't say more than that. And so what we decided a few years ago, can you start the video? Let me see. Where do I start? This is an educational video demonstrating sentinel inguinofemoral lymph node detection in vulvar cancer, highlighting the novel use of real-time near-infrared imaging for sentinel lymph node evaluation. Injection of dye occurs in the operating room at the time of examination under anesthesia. This allows the dye sufficient time to disperse into the inguinofemoral lymphatics. Two to three milliliters of ICG solution is injected in the dermal layer of the skin at the leading edge of the lesion bilaterally, creating a wheel in the dermal layer. An additional one to two milliliters of ICG solution is injected bilaterally to ensure lymphatic uptake of the dye. If blue dye will be utilized, as seen here, the same protocol is followed. When sentinel lymph node detection is performed, both radiolabeled isotope and blue or ICG dye should be used to aid in identification of the sentinel lymph node. In this case, radiolabeled technetium-99 has previously been injected, and lymphocentigraphy performed. With the use of a gamma counter, uptake of the technetium-99 is confirmed in the operating room. The surgical site is subsequently marked. This is repeated on the contralateral side. Illuminescence of ICG can be seen transdermally, as shown here on the patient's right side. The ICG is viewed on the video screen as bright white on a dark background. This is of considerable benefit over blue dyes, where uptake of the blue dye can only be visualized after the dissection has begun. Additionally, this helps the surgeon localize the region of the sentinel lymph node before an incision has been made. After confirming the uptake of ICG and location of the sentinel node, the dissection is begun. While the location of the node can be assessed intraoperatively by the gamma probe, seen here now draped, it does require that the dissection is paused while the area of highest signal intensity is localized. Conversely, real-time near-infrared imaging allows the surgeon to continue the dissection while visualizing the location of the sentinel lymph node. While ICG uptake is visualized as white on a dark background here, the system can be customized to allow color with red hues indicating higher ICG uptake, as seen here. With the video output playing in real-time, the surgeon can visualize the spatial relationship of his or her instruments to the location of the sentinel lymph node. With the location of the sentinel lymph node confirmed, the dissection is continued. All right, so for time's sake, you get the idea there. So, you know, this video we made a few years ago already, and we've already modified it. We've had a learning curve. We've modified a technique a little bit. That detector you saw there, we no longer use that. We use this handheld one, which is available. But there's a lot of near-infrared imaging technologies available throughout the world for intraoperative use. So this is the first report I could see of using ICG for SLN. It was by Dr. Crane in 2011. They used ICG, the technetium, and the blue. They mixed. The concentration was a little too dilute, probably, in my opinion. And they mixed the ICG with the blue, which I think you shouldn't do. And then they detected sentinel nodes in 90 percent using ICG. Seventy-two percent were detected with the blue. The only issue here, which we still struggle with, which is the learning curve to this and sort of the nuances of this, is how do you find this transcutaneously? And obviously, in that patient I showed you there, it wasn't so straightforward. And there is a trick to it. We've reported our sort of outcome with sentinel node mapping at our institution a few years ago with Dr. Vance Broach, one of my junior partners. And we've used ICG now, at least at the time of that publication, in 85 patients and done over 150 groins with ICG in various combinations. As we've been learning, we've added it to the blue and technetium. Then we got rid completely of the blue. And in some cases, we've gotten rid of the technetium altogether. And this is sort of how it's evolved over our time. We were doing the standard blue technetium for many years. We did our first use of ICG in 2012. And now we use ICG pretty much for all of our cases. The rate of use of blue has dropped dramatically, and we still are trying to figure out the role of technetium. But the majority of our cases, we still use technetium. This has been our outcome that you can see here that with ICG alone, you actually have a very high detection rate for sentinel nodes. It's not 100 percent as when you add a technetium, but it's pretty close. And this, again, keep in mind, is part of an early learning curve that I've shown you. There's been a meta-analysis looking at the use of ICG. These are all relatively small numbers with the largest here as being ours. And again, the bottom line here is that ICG seems to have a very high rate of detection as does technetium, but blue is very poor. So the practical tips here is if you're going to do this in your practice, you want to add it to what you do now. You don't want to just flip over to something brand new, okay? So you never just say, I'm going to just start doing ICG, of course. I think that the concentration should be 25 and 20 mLs. That's what we use, similar to everything else we do in GYN, and it seems to be sufficient. Some of those studies looked at adding human serum albumin, which is supposed to augment the effect of the ICG. It's unnecessary and cumbersome. We don't use blue at all, so this is not even an issue, but I would not mix the two together in the same syringe. You do separate injections. I like to inject, as you saw in that video, prior to patients draped and prepped because I like to see with the handheld and sort of start marking the patient, but that's a stylistic thing. You know, we talk about the standard being injecting around the tumor, but you know, that's really unnecessary. There's no science behind that. The lymphatics of an organ are the lymphatics of an organ. The tumor does not change those lymphatics. So you're mapping the vulva, so if it's a unilateral, you can inject the leading edge of the vulva near the level of the clitoris. If it's a midline lesion, then you inject both sides. This whole thing about injecting around the tumor is what we still say is standard. I'm not changing that standard, but you have to rethink that. And then you have to be careful when people start to dissect that they also don't start looking for a node too soon, especially in a heavy patient. This is an easy one for ICG. This is a very thin patient, and you can see how nice this looks. The central nodes are highlighted in a blue. Unfortunately, that's not the majority of cases. When you see this, you're very extremely happy, and you can see there would be no role whatsoever for technetium or anything else there, but this is not usually what we see. This is more what we see, like you saw in that video there. It's kind of just a glow. So over the many years of doing this, what you realize is that you kind of follow the glow that's in the lymphatics and the subcutaneous tissue, and then when it stops, it's going deep into the lymph node, and then you'll find your lymph node right there. That's where you make your incision at the end of that glow. Now we didn't learn this just because I woke up one day and learned it. This was a little bit of trial and error, and continue to use the technetium. So you follow the glow, the central nodes at the end. There's no change for concentration just because the patient's heavier. This is where technetium, especially when you start to introduce this, is going to probably be the most helpful. And again, spy mode, forget the overlay. You're not going to see any overlay of anything. The spy mode, which is this dark mode, is the best mode to do this in. And again, these are usually the cases we deal with the majority like this, but if you follow that glow and you make the incision at the very end of that glow, those are lymphatics, you'll see a bright SLN there. We are about to open a prospective trial to see if we can completely replace technetium altogether. This is in development right now with my junior partner and I'm the co-PI. We're going to inject everyone with a Technetium 99. The surgeons will be blinded to the Technetium results, lymphocinthogram, SPECT CTs. We will then do the mapping with the ICG. Once we think we've found the SLNs with the ICG, we'll then look at the SPECT CT and then put on the gamma probe to see if we've missed anything. There's this whole thing now about MIS groin dissections and SLN mapping. As many know, I'm a big MIS robot fan, but I still don't know how to feel about this one. To be determined, maybe in a couple of years I'll come back with something different. Anyhow, I'm right on time and thank you very much. Thank you very much, Mario. That was a great talk and a great short video. Next, we will hear from Dr. Alexandra Taylor from the UK. She will discuss aspects of adjuvant management. Alexandra. Thank you very much. Here are my disclosures. I've been asked to talk on is there a margin where adjuvant radiation should be considered and isolated tumor cells to treat or not to treat. I have to say this was my reaction. I'm not sure we can get consensus, but I will give you my opinion. In terms of is there a margin for which there's a higher risk of recurrence? Traditionally, we've aimed to get at least eight millimeters pathological clearance, and if not, consider re-excision or radiotherapy if not feasible. We know a lot of the local recurrences that we see are actually second primaries. Recent studies have been challenging whether this margin is truly necessary. Here we have some recent studies, all with over 100 patients who have looked at this question. Different inclusion criteria, different use of radiotherapy in the adjuvant setting, so it does become a challenge. We can see that the local recurrence is in keeping with past studies. These groups all looked at different comparators in terms of margins, which I had to summarize what they were looking at, and to see if there was a cutoff or a comparison. In terms of conclusions, again, we have a range. We have some groups highlighted here who have seen a higher recurrence rate, particularly at two to three millimeters or less, and across the board, there are very few patients here who have those margins who did not get adjuvant treatment. Other groups have shown no difference, but also highlighted that other factors, such as the presence of DVIN in the margin, is actually a higher risk factor. I'm just going to focus in on the largest cohort with the longest follow-up from Australia, in which the headline would be, there's no difference in the margins, 23 versus 22 percent at eight millimeters. But actually, if you hone in on the margins, those less than five millimeters, that if they had further treatment, be that re-excision, or in particular radiotherapy, that the recurrence came down to 40 percent to zero. So actually, you do need to sort of look closer at the data, and that is consistent with other studies that would suggest that giving radiotherapy does reduce the risk of recurrence. The largest cohort we have are for margin-positive patients, and this is the National Cancer Database results, which showed a survival advantage, overall survival benefit at three years of giving adjuvant treatment. But what this study also looked at was, is there a dose response? And this clearly shows that giving over 54 gray actually increments in terms of your benefits, so we need to give adequate dose when we are giving treatment. Does the margin matter at all? Is it other risk factors we should take into account? And this is the German AGO Care subset group of patients, where they compared those that received radiotherapy to the vulva, who were all node-positive. And in the vulva-treated group, there were much higher adverse features, but despite that, this cohort had a survival advantage in terms of disease-free survival and overall survival with giving radiotherapy that included the vulva. Now, does that benefit have a cost? It does, and we all know that giving radiotherapy, we need to think about toxicity. And this is what we can see in terms of skin reaction is the challenge for patients, but it does resolve at four weeks after treatment. Very early, you get resolution. And I think we have to highlight that we just don't see the reactions like this when we're starting to use new techniques. So with anterior posed fields, then we would see a hot spotting actually within the skin of the vulva, which is where we get that toxicity with IMRT. You can deliberately reduce your dose around the skin and give a much more even dose, and it reduces the toxicity. But if we don't treat these high-risk patients, do we have effective surveillance and salvage? And that's where the multidisciplinary team sort of comes in to consider this, because I think we'd all agree that there's a big difference between a two-millimeter margin on the labia that we monitored versus a deep margin by the urethra or anus where you're unlikely clinically to detect recurrence and that salvage would be more challenging. So we need to consider what your salvage options would be. So in summary, I would say, is there a margin? Well, there is a high risk of recurrence, certainly with an involved margin two to three margins and possibly higher. Radiotherapy does reduce the risk of recurrence, but you need to give adequate dose. You can consider surveillance or radiotherapy balancing toxicity risk, but we also need to think about other factors, multifocal disease, particularly lymph node involvement, and also precursors, so devin or lichen sclerosis. In terms of the second conundrum, we've already heard about this in terms of isolated tumor cells, and it is something that we're considering for lots of tumor types. And as we said, we have pretty established pathways now for management of a macrometastasis or a micrometastasis, and the question comes, are we going to treat ITCs as N0, as we do for many other tumor types, or N1? Thinking about the mechanisms, why wouldn't we treat IT, why would we call it N0 if there's no increased risk of recurrence or a very low risk of other lymph nodes being involved when other factors predict for adjuvant treatment or there's a high risk of systemic relapse? And that's what we see in breast cancer, and as we heard in endometrial cancer, histological factors may also predict for recurrence. Sort of linking back to what we've discussed on margins, when will additional treatment toxicity, does that outweigh our benefit, or do we have effective surveillance and salvage? Why should we treat it as N1? And again, in general, and I think you'll see where I'm going here, is lymph node involvement is an independent prognostic factor. The pattern of recurrence that we're dealing with is loco-regional, predominantly rather than distant. Additional treatment does reduce the risk of recurrence, and local recurrence is very difficult to salvage. What is our data? Well, again, we've heard it's really congratulations to Micah and the Groins V group in that this is where we have our data, and we can see from Groins V that with ITCs, there is no threshold for the size of nodal metastasis, which there isn't a risk of additional metastases, although it does increase quite significantly as the nodal metastasis increases in size. In Groins V2, as we've heard, the ITCs were treated exactly the same as micrometastases, so we do consider it N1. Within the study, 79% of patients had radiotherapy as per protocol, and 10% had IFL instead. In terms of groin recurrence, as we know, radiotherapy significantly reduced the risk of recurrence, and looking particularly at the group with ITCs, and this is our one publication, I think, where we look at ITCs, that the cohort that had radiotherapy, there's no recurrence, very small data, but with no further treatment, one out of 11 patients did relapse. Again, really just underlining the Groins V2 study. In terms of toxicity, with radiotherapy, we see very minimal late toxicity, and again, where conformal radiotherapy was used predominantly in this study, with IMRT, it would further reduce your doses, but underlining that surgery, that inguinal femoral lymphadenectomy is far more morbid for the patient than sentinel lymph node with radiotherapy. And part of that, just touching on, is which lymph nodes would we include? Well, conventionally, if we've got involved inguinal nodes, we would include the inguinal femoral nodes, but also the pelvic nodes, external iliac nodes, ipsilaterally. In the Groins V2 protocol, only the distal external iliac nodes, the inguinal nodes, were included, although with the radiotherapy technique that was predominantly used, probably quite a lot of internal iliacs were also included. Do we have any data on which nodes to include? Is it okay to not treat the pelvic nodes? Well, it's back to the AGO group, where they looked at patients that, again, were node positive, and of these, over 100 had a pelvic lymph node dissection as well, and we can see that those with micro metastases within that cohort, small nodal metastases, they noted no incidence of any positive pelvic nodes, and therefore, we can be reducing the area we treat and just concentrate on the inguinal region. And my final point is, do we have effective surveillance and salvage options? Well, I think we all agree that clinical examination can be very unsatisfactory to pick up early nodal recurrence. With imaging, we have a low sensitivity with cross-sectional imaging, and probably the most sensitive is ultrasound, but you need expert radiologists for this. And our salvage, again, pretty dismal in general for lymph node recurrence, although if picked up when asymptomatic, can be effective with debulking surgery and radiotherapy, and we all know how difficult it is to manage uncontrolled disease. So in conclusion, should we treat it as N0? I don't think we have anything to support any of those criteria to be N0, and we do have a large study, so my conclusion is, yes, we should treat it as N1, but the data is limited. Thank you. Great presentation, Dr. Taylor. Thank you very much for that. The final presentation comes from Dr. Danielle Vajkas. She will be presenting on vulvar melanoma considerations for surgical and adjuvant treatment. This will be followed by a 10-minute Q&A session. Good morning, everyone, and thank you very much for inviting me to speak here today. I can't, are the slides up? Oh, okay. Sorry, I couldn't see them. Okay, so we're going to be totally changing gears here, and we're going to move towards vulvar melanoma, and I was specifically asked to talk about vulvar melanoma updates for the gynecologic oncologist, so excuse me if there are other specialists in the audience today. Oh, is it this one? Okay, so these are my disclosures. So vulvar melanoma, as we all know, is a very rare tumor, and there's really a paucity of data specific in vulvar melanoma on how best we are to manage our patients. We therefore need to base most of our recommendations on studies either in patients with cutaneous melanomas or those assessing the treatment of patients with other types of mucosal melanomas. I'm going to focus this talk on the data to support what we as gynecologic oncologists need to know to better treat our patients. So the mainstay and first step in treating patients with vulvar melanoma is surgical resection. The goal is always an R0 resection, as it is almost always in oncology, and it can definitely be challenging due to the proximity to critical anatomical organs. This study, which included one of the largest cohorts of mucosal melanomas, looked at 444 patients with mucosal melanomas from different sites. They found a higher rate of both local relapse and distant metastases in those with an R1 or R2 resection, which is seen here in red, in comparison to those with an R0 resection, seen here in blue. They further demonstrated an inferior overall survival in those with an R1 or R2 resection in comparison to those with an R0 resection. They looked also at a multivariable analysis, and margin status was found to be an independent prognostic factor, and therefore our goal at time of primary resection is to achieve negative margins. So our next surgical question is in regards to sentinel lymph nodes. We know that lymph node involvement is one of the most significant negative predictive factors in patients with melanoma, and the morbidity associated with complete dissection is definitely considerable. Therefore, Morton and colleagues performed a study called the multicenter sentinel lymphadenectomy trial, MSLT1, and this was in cutaneous melanoma, and they set to assess, they set out, sorry, to assess the role of sentinel lymph node assessment versus observation in this cohort of patients with cutaneous melanoma. They randomized 2,000 patients to either wide local excision with sentinel lymph node biopsy and full dissection, if a positive node was identified, versus wide local excision and observation, in which a full lymph node dissection was performed at time of local recurrence. Sentinel lymph node was identified in almost 100% of patients. In the left Kaplan-Meier curve, we can see that disease-free survival was significantly better in the sentinel lymph node biopsy arm. The right Kaplan-Meier curve demonstrates an improved melanoma-specific survival seen when comparing patients with positive nodal disease. The yellow line depicts those in the observation arm that had a nodal recurrence, sorry, that had a nodal recurrence, and the orange line depicts those in the sentinel lymph node arm that had positive nodes. Those in the sentinel lymph node arm had improved survival with a hazard ratio of 0.56. This cemented the incorporation of sentinel lymph node biopsy in patients with cutaneous melanoma and has been adopted in those with mucosal melanoma when feasible. They further saw that only 20% of patients with a positive sentinel lymph node had additional positive nodes identified when they continued and did the full dissection. This led to two additional large RCTs in patients with cutaneous melanoma, the DCOG SLT study out of Germany and the MSLT2 study out of the U.S. Both studies randomized patients with a positive sentinel node to either observation versus a complete dissection. Both studies confirmed no difference in overall or melanoma-specific survival between the arms and an increase in morbidity in those undergoing full nodal dissection. Therefore, a full dissection is not recommended unless enlarged lymph nodes are identified and these should be removed to improve disease control. Due to the high rate of distant metastases, but while taking into consideration the challenges in obtaining sufficient margins, the role of adjuvant radiotherapy has been questioned. The systematic review looked at studies comparing surgery versus the combination of surgery and radiation for patients with head and neck mucosal melanomas. They showed that the addition of adjuvant radiation improved local control with a hazard ratio of 0.36. However, they further demonstrated no difference in overall survival as seen here between the groups. Therefore, concluding that radiation improves local control without improving survival. It can further play a role in cases with unresectable disease or palliation. However, we really need to look at it as a, sorry, for local control but not with no benefit in survival. Vulvar melanoma, as we know, has a poor prognosis with a propensity for distant metastases. Therefore, adjuvant systemic therapies are needed. Historically, patients with mucosal melanomas were excluded from large melanoma trials even though their mutation profile is unique and distinct from that of cutaneous melanoma with a higher rate of C-kit mutations and a much lower rate of BRAF mutations. Lian and colleagues from China successfully completed one of the first large RCTs specifically in patients with mucosal melanoma. They randomized 189 patients to one of three arms, observation, interferon, alpha, or combination chemo, which was temzolamide and cisplatin. About 10% of patients had a vulvar melanoma in this cohort. This study showed improved progression-free and overall survival in those treated with combination chemo, depicted here in the yellow line, in comparison to both interferon and observation shown in blue and black. This study opened the door to performing trials specifically in patients with mucosal melanoma, demonstrating feasibility in this rare tumor type. The molecular profiling of mucosal melanoma has shown a C-kit mutation rate of about 30 to 40 percent, which led to the initiation of a phase two single arm study of Sinitinib. 52 patients with mucosal or acrylomelanomas were accrued. And this study demonstrated disease control rate of 44%. These encouraging results led to the initiation of the ECOG ACRIN E2607 trial, which had two stages. Stage one included patients that were CKIT positive or negative, and those with cutaneous or mucosal melanoma. Due to a low response rate, they limited stage two to mucosal melanomas and acrylomelanomas who were CKIT positive. Patients with vulvomelanomas were eligible. The overall response rate in those with a CKIT mutation was only found to be 18%, and this study was deemed negative. Immunotherapy has changed the landscape for cutaneous melanoma, improving survival for patients in both the adjuvant and recurrent settings. These are just some of the trials that have brought to FDA approval of immunotherapies in patients with cutaneous melanomas. In all of these trials, patients with mucosal melanomas were excluded or highly underrepresented. In 2017, DeAngelo and colleagues published this pooled analysis of patients with mucosal melanomas that were treated with immunotherapy in any of the RCTs that were originally planned for patients with cutaneous melanomas. On the right is a Kaplan-Meier curve with the corresponding response rates for cutaneous melanoma, and on the left, those of mucosal melanoma. They showed a response rate for patients with mucosal melanoma of 23% to single-agent PD-1 inhibitors and an impressive 37% to the combination of PD-1 and CTLA-4 inhibition. This was one of the first papers to demonstrate the response rate of immunotherapy in patients with mucosal melanoma. In 2019, a Phase 1b study conducted in China assessed 29 untreated advanced mucosal melanoma patients with a combination of the VEGF-directed tyrosine kinase inhibitor excitinib combined with PD-1 inhibitor turopalumab. They reported an overall response rate of 48% with a median progression-free survival of 7.5 months. The response rates in those with PD-L1 over 1% was 70% versus 42.1% in those with PD-L1 expression less than 1%. Adverse events were similar to other combinations, GI, proteinuria, and hypertension. So we know that patients with mucosal melanoma have a very poor prognosis and they have distinct mutations. Therefore, extrapolating for cutaneous melanoma is challenging and definitely not accurate, and trials specific for this population are definitely needed. Currently, standard adjuvant therapy in cutaneous melanoma is PD-1 monotherapy. Studies in advanced-stage mucosal melanoma have shown very encouraging overall response rates with single-agent PD-1 inhibition of 20 to 25%, combination with ipilimumab of 37%, and combination of excitinib and turopalumab of 48%. This data has led to the planning and the recent opening of A091903, a randomized phase two trial of adjuvant nivalumab with or without cabozatinib in patients with high-risk resectable mucosal melanoma. This is a partnership between multiple collaborative groups and one of the first randomized studies in patients with mucosal melanoma. It is led by Alliance and is open to recruitment as of about a month ago. Patients with untreated mucosal melanoma or recurrent resectable that have undergone surgery with or without radiation are stratified by primary site, PD-L1 high versus low, node status, and receipt of previous radiation. Patients with an R0 resection are randomized one-to-one to nivalumab with or without cabozatinib, and those with an R2 resection or unresectable disease are eligible for ARM2, in which all patients are treated with a combination. The primary objective is to compare the efficacy of adjuvant nivalumab versus nivalumab plus cabozatinib in patients with mucosal melanoma. The primary objective will be measured as a comparison of duration of recurrence-free survival between the arms, and here you can see the additional secondary and exploratory objectives. So what are the take-home messages? From a resection perspective, as in most of our other tumors, really our goal is R0 resection. Sentinel lymph node biopsy is recommended. Complete dissection is actually not something that is recommended. And adjuvant radiation is not standard of care, but can be considered for local control. Immunotherapy at this point in time looks very promising, and we hope that you will consider opening A090103 at your center. Thank you very much. Thank you. Thank you, Dr. Ficus, for this excellent overview on treatment of vulvar melanoma. The floor is open for questions now. Thank you. Estelle Limberis from NYU Radiation Oncology. I just have a question in the updated vulvar cancer staging. We know that patients with pelvic nodal involvement, even comparing to the designation of 4B in the previous staging, and now also maintaining that as a designation in the current staging, can have a five-year overall survival with IMRT and radiation of even up to 45%. Why wasn't there a consideration to include that as a separate category, keeping regional nodes only as inguinal femoral and not actually defining pelvic nodal disease, rather than lumping that still in 4B? Thank you for your question. I didn't find the consideration of not including the pelvic nodes, but so for the stage three, they only used inguinal femoral nodes, and that's what we can assess with our central node procedure. I think the pelvic nodes will come up with additional imaging if we suspect a metastatic disease in which we can think of if the tumors are larger than four centimeters. So I think it's important to search for the pelvic lymph nodes if we have other risk factors for this metastasis. Hi, the question is to Mario. Do you use only ICG, or you still use technetium and ICG for central nodes? Yeah, we go back and forth on that. Right now, we made a service policy that we're gonna do technetium still until we figure it out even better across the board. Some of us do a lot more of the central node mapping than others in our group, so we want everyone to still use the technetium until we finish our prospective trial that we are about to open, and then we will, well, it depends on what that shows, but right now, we are using technetium. The short answer is yes. Now, in a very thin patient, it's really unnecessary, so a very thin patient, I personally have avoided the technetium, but the general is that we are still doing technetium for now. Okay, that's at MSKCC, but is there enough evidence to use ICG alone at other centers? No, no, no, I don't think so. Especially if you're gonna start it for the first time, you absolutely should not do it by itself. I don't think there's enough yet to, there is a learning curve to it, especially your thicker groin spaces. There's a little bit of a technique and a learning curve to it. It's not so straightforward as you'd think. It's not like the cervix and the metrum are directly looking at the lymphatics, so no, I would not just replace current standards right to ICG right now. Thank you. Question in the back, please, and then the front. Good morning. Thank you for a wonderful presentation. Constantine Gorlick from Brooklyn. If you have a patient with vulvar melanoma, the primary lesion is resected with a microscopic positive margin, groin nodes are negative, and there are multiple sites of melanoma in situ found which are not resected. How would you manage this patient post-op? Would you give immunotherapy? So are the, sorry, just a question. So in regards to the melanoma in situ, were those areas resectable or not resectable? No, they're not resectable. Yeah, so I mean, that's, it's definitely challenging, and we definitely talk with our medical oncologists and try together to make a decision as to which patients should have immunotherapy, yes or no. We definitely want to, we don't know yet what the answer is in regards to adjuvant therapy. What is the best adjuvant therapy, especially in this patient, as you're mentioning, who has a sentinel lymph node which is negative? I don't think just having that small positive margin would be an indication for it. Obviously, there is an option to observe the patient. Hard to say. It depends on other factors, of course, also the thickness and other prognostic factors. Thank you. Good morning, Owen. So my question is quite simple. I just wanted to know, when we are talking about close margins and monitoring of those close margins, how closely do we monitor those margins, and how do we monitor those margins? Because they look angry as it is. Are you recommending taking a smell, or you want imaging, or what would be your recommendation, and how frequent? Well, I was also looking at Maria as well, in terms of gynecologists. Generally, it's clinical examination is by far the best way of monitoring these patients. How frequently, I don't know how often, but certainly when we're looking at groin nodes, if patients are at high risk initially, we actually do monthly ultrasound because in terms of nodal recurrence, it tends to occur in the first six to eight months, and often very early if there's a risk in the studies. And so we would very closely monitor initially. And in the studies that I showed in terms of margins, they did show that those that had a very close margin and relapsed tended to have more aggressive disease and had worse survival. We saw that in the groins B study, and also in some of the cohort studies. It also depends on what you, I mean, HPV-associated stuff is way different than the DVIN, lichen sclerosis, which is a nightmare. Those are the worst patients I have to manage. Plus, they can't tolerate radiation therapy because the skin's already so bad. So I think it also depends on a close, completely negative margin, not in lichen sclerosis, and no DVIN or no VIN3 at the margin. That's a different person than someone who's got a negative cancer margin, but has VIN3 to the margin, or in the background of lichen sclerosis. Since we've moved away from radical total vectomy, the Texas longhorn incisional stuff, we've now traded that lower recurrence, quote, unquote, and exceedingly high morbidity for the possibility of repeated resections in these women. So I will see them every three to four months for the first two to three years, close physical exam. Again, the hard ones are those who have the lichen sclerosis and sort of just really angry skin, as you mentioned. But the HPV-associated ones are, I'm not as worried about if they have a clearly negative cancer margin. And it doesn't matter if it's one, two, or three. And most of the recurrences are local in those patients anyway, which if you detect them early enough, then you can just re-excise. Question in the back, and then front, please. Yes, hi, my question actually was exactly what Mary just described. This was the relation between the margin status and indications of radiation therapy. It does not seem like you are making a distinction between HPV-related vulva cancer and non-HPV, which in a way are different diseases. Do you respond differently to radiation therapy and have different toxicity profile as well? So I wonder if you have an answer to that. Yeah, I think I did touch on, I mean, we could see in the studies that having DEVIN at the margin has a much higher risk of recurrence. And therefore, it is a factor that you have to consider. In terms of response to radiotherapy, as it stands in terms of dose, we do not differentiate. If we look at head and neck cancer, de-escalation of dose did not impact with the HPV-related tumors. Although we do see in primary disease that probably you have to escalate higher in the non-HPV, but I'm not sure in the adjuvant setting we have the data to differentiate. I have a question for Dr. Mario Leitai. I'm from the Netherlands, University Medical Center Groningen and I wonder what problem you want to solve with your ICG green procedure because I don't get how you can improve or how you want to improve the efficacy and the safety and the high sensitivity of the current procedure by ICG green. We have some experience. We participated in the crane study, but I don't see it yet. Maybe you can explain it. Well, I think that not everybody's gonna use it. It's just a technique like any other. I mean, it avoids the technetium, which is a radioactive compound. It avoids the costs of SPECT CT and all those imaging studies, which are not free. So it's cheaper overall. The ICG is very inexpensive and you can do real-time imaging because the blue is not good enough for real-time because you can barely ever see that. So there's a lot of advantages in my opinion to doing it. Plus, I don't know, getting injected while you're awake with technetium is absolutely no fun. Our nuclear medicine people are calling me all the time as to figure out where and what to inject. It's a nuisance. So hopefully that's a list that I've given you for in my mind why I think it'd be better for me, but no one has to change. I'm not trying to say that I'm gonna change the world by making everybody do ICG. It'll be just, we want to just show it's another viable option and then surgeons will decide what they think is best in their hands. And aren't you afraid because you don't have a lymphocytography before, so you don't know how many nodes there are or you need to find? No, because everyone thinks that the problem with lymphocytography is that unlike what we learned with cervix endometrium, people think that every hot node needs to be removed. Those aren't all sentinels. Those are secondary lymph nodes. So because we can't see the channels directly, that's why we rely so much on that for vulva. But for cervix, we no longer take out all the green nodes and call them all sentinel node because we know which are the true sentinel nodes. So really those extra nodes are not usually true sentinel. They're just other draining lymph nodes because you also do this lymphocytogram and you have pelvic nodes that take up the dye. So are you going after pelvic nodes as sentinel nodes? I know, I know. I've performed the procedure for 25 years now. No, not for you directly, but for the audience. I'm not talking about the secondary nodes, but I'm talking about the true sentinel nodes. And sometimes there are two nodes. And I showed you that picture with the ICG where there was three sentinel nodes on the left side with the ICG alone. Okay, thank you. Last question, Dr. Koh. Thank you, thank you to all of you all. I've always been faced with this conundrum of ITCs which have been brought out. It is interesting that all of that is, I think, based on one patient who had pathologic findings in groins V1 who had this one out of 24 who had other non-sentinel lymph nodes. So it's a 4% failure rate, and I get that. But yet in groins V1, groins V2, we accept a 2% to 2.5% failure rate as being successful. So I guess, would we ever have the courage to reinvestigate that population again without consigning all patients to further aggressive treatment based on a single pathologic case? Yeah, I did put my disclaimer on how little data there is. And it was more just thinking on mechanisms and pathways. I don't, I absolutely agree. I don't think we have all the data, but I think we also know how involval cancer, in particular, control is important. But I agree, I think it's an open question. Yes, and I also think it's just not enough data now to omit the radiotherapy in the isolated tumor cells and it's only a few cases, but yeah, we need more data. And maybe it's a single case in a large series of all negative patients, but we don't know that yet. And when it comes to avoiding groin recurrences, I think we should be better safe than sorry. And maybe in, like in endometrial cancer, we have to isolate the tumor cells and like in endometrial cancer, we have to identify other factors that can help us in deciding if adjuvant treatment is necessary, like HPV status or LVSI in the tumor. I think that it will help us deciding for adjuvant treatment. Thank you all so much. Thank you to this outstanding panel. That was a really wonderful session. We will now have a 10 minute break. Please be back here at 1020 for our special guest speaker, Dr. Tal Zaks, delivering the keynote lecture for our meeting. Thank you so much.

Vulvar Cancer Master Session

Modern Management

Dr. Lillian Jian

Dr. David Gaffney

Dr. Micah Oonk

FIGO 2021 staging

indocyanine green

adjuvant management

vulvar melanoma