Europe. Welcome to this IDCS master session on vulvar cancer. It's a great pleasure and honour of course to have this meeting. The plans were to have this from Rome and so also to be in Rome but unfortunately due to the corona pandemic that is not possible. But still I'm quite sure that we are going to have a very interesting and exciting session on vulvar cancer together with you. My name is Aad van der Zee from the University Medical Centre Groningen in the Netherlands and I will be moderating this session together with Dr. Anuja Yingran from the United States and Dr. Sven Manner from Germany. I think we put together a great master session for today. We will have time after the presentations for a discussion and question and answers. So throughout the different presentations please submit your questions through the Q&A feature and then we will do our best as moderators our best to address them at the end. So without any further ado it's now time to get started and our first speaker is Dr. Linda Nooy from the Leiden University Medical Centre in the Netherlands. Dr. Linda Nooy is a gynecologist from Leiden and in 2018 she presented a very nice thesis, completed a very nice thesis on translational research in vulvar cancer and we are very happy that she is willing to start off with the first presentation. Dr. Nooy please go ahead. Thank you for the introduction Dr. van der Zee. I was asked a few days ago to give a presentation in this vulvar cancer session and as was said in the introduction I work as a gynecological oncologist in the Leiden University Medical Centre in the Netherlands and I was assigned to give a presentation on translational research in vulvar cancer from bench to the clinic within the next decades. So in this presentation I would like to give you an overview of the research that was performed by the research group of which I could be part of and where I did my PhD and I want to take a look with with you if we indeed can incorporate this translational knowledge into clinical practice in the coming years. So I have nothing to disclose. First I want to take a look at you with you at the pathogenesis of vulvar cancer and as most of you will know vulvar cancer can typically be subdivided into HPV positive or HPV dependent vulvar cancers which comprise the smallest group of vulvar cancer patients around 30 percent and share a lot of similarities with the carcinogenesis of cervical cancer. In this vulvar cancer group, vulvar, high grades, squamous inter-epithelial lesions are considered to be the precursor lesions for the HPV positive cancers. On the other hand, the molecular mechanisms leading to HPV independent or HPV negative vulvar cancers remain largely unclear and complex. Inflammatory dermatosis such as ligand sclerosis are considered to be etiological drivers and the precursor lesion is considered to be differentiated vulvar intra-epithelial neoplasia which is often identified in the adjacent skin next to the vulvar cancer and is thought to precede most of the HPV independent vulvar cancers. We know that mutations in the tumor suppressor gene TP53 are involved in a significant proportion of these tumors. However, there are also vulvar cancers that are HPV independent and p53 wild type and these vulvar cancers probably have a different molecular background. So when our research group started, the genomic landscape apart from the known mutations in TP53 were poorly defined and research was also hampered by inconsistent reporting of HPV status and limited application of NGS technologies. We considered that understanding the molecular biology especially of the HPV negative vulvar cancer could help us to differentiate between the HPV positive and HPV negative diseases and gain knowledge about the pathogenesis of these two entities. So our research group started looking into the molecular background of these vulvar cancers by starting an investigation on the absence or presence of point somatic mutations in vulvar cancers. My colleague, Dr. Trietsch investigated 25 vulvar cancer samples with a panel that was called Ginkarta and was developed to detect point somatic mutations in a specific set of genes that was selected based on publications at that moment of somatic mutations in gynecological malignancies. And what we saw in her research was that she could identify three different groups of vulvar cancer. The HPV positive group that did not comprise any of the point somatic mutations and the HPV negative group that harbored P53 mutations, but also a group that was HPV negative and P53 wild type. And this research was actually the start of my future PhD research in which we wanted to look at this in more detail, but also to further investigate molecular backgrounds, especially from the HPV negative and P53 wild type vulvar cancers. Since they developed the Ginkarta panel, a huge development in next generation sequencing took place. And we decided to not use the Ginkarta panel, but to develop a targeted next generation sequencing panel, which covered 17 different genes and which we selected based upon publications on mutations in vulvar cancer at that moment, but also on known mutations in head and neck cancers, which share a lot of similarities with vulvar cancer. Head and neck cancers also have HPV associated and HPV independent pathway, which is associated with mutations in P53. So first, we looked at the mutational profile of vulvar precursor lesions with a focus on the HPV negative vulvar precursor lesions. And what we saw was that there was a clear difference in HPV positive and HPV negative vulvar precursor lesions. We found that there were less somatic mutations in the HPV positive precursor lesions. And that the HPV, sorry, it was a bit too fast. And that we could identify three different types of precursors, the HPV negative P53 mutants, but also the HPV negative and P53 wild type vulvar precursor lesions. So we further looked into 36 vulvar cancer samples in order to see the mutational profile of these cancers. Again, we saw a clear difference between the HPV positive and HPV negative vulvar cancer group. The somatic mutation frequency in both groups were actually comparable, but we saw that multiple somatic mutations were much more frequent in the HPV negative vulvar cancers. And when we looked at these groups in more detail, again, it was striking that we could identify a third possible molecular subtype of vulvar cancers, which consisted of the HPV independent vulvar cancers, which were P53 wild type. And we saw many mutations in NOTCH1 and HRES in this specific subgroup. So of course, the important question is whether such a subdivision in three different molecular subtypes could be validated also by others. And also if this subdivision indeed has clinical consequences. So first I want to focus with you on studies that were published after our research and then I want to show you data that indeed indicates that the three molecular subgroups have a different clinical behavior. So shortly after the publication of our study, ViroPulse published a study in which they performed next generation sequencing using the cancer hotspot panel in 43 vulvar cancer patients. What the authors found was that there was a high mutation rate in both HPV positive and HPV negative vulvar cancers. And they found a clear difference in the genes harboring somatic mutations between the HPV positive and the HPV negative group. The HPV negative tumors were found to have mutations in P53, HRES, PI3 kinase and CDKN2A. While the HPV positive patients had oncogenic mutations in PI3 kinase, FGFR3 and P10. Another study that was published one year later performed whole exome sequencing on 15 vulvar cancer samples. And what the authors found was that there were more somatic mutations in the HPV negative vulvar cancers. And that the profiles of the driving mutations for HPV positive versus HPV negative vulvar cancers did overlap, but were not identical. Another study that I want to show you was published one year later. And in this study, they performed next generation sequencing with the oncomine comprehensive panel on 32 vulvar cancer patients. And they found a clear difference in somatic mutations between both vulvar cancer groups. HPV positive vulvar cancers comprised or harbored mutations in PI3 kinase, while the HPV negative vulvar cancers harbored mutations in P53 and CDKN2A. A review published afterwards gave an overview of all the studies that were published at that moment, which used next generation sequencing on vulvar cancer. And at that moment, 201 vulvar cancer tumor samples were examined using some type of next generation sequencing. The authors found that mutations in P53, CDKN2A, PI3 kinase and HRES were most commonly analyzed and detected. And they also saw that there was a clear difference in the molecular background of HPV positive versus HPV negative vulvar cancers. I think that by now, we can establish that there's a subdivision at least in HPV positive and HPV negative vulvar cancers, and possibly a third molecular subgroup. The important question remains whether or not this has clinical consequences for daily practice, and if we can indeed incorporate this knowledge into the clinic. So the HPV status has been subject to debate already for many years on how it influences prognosis. If we look at other tumor types, this prognostic influence of HPV status has been established already. Again, I've looked at two tumor types that share many similarities with vulvar cancer, head and neck cancer, as I mentioned before, but also penile cancer. And in those tumor groups, it is evident that HPV positive patients have a better prognosis compared to their HPV negative cancers. And in head and neck cancer, this knowledge is already used in daily practice and treatment plans are being composed partly on the absence or presence of HPV. So can we also state this for vulvar cancer? At that moment, we decided to collect follow-up data and perform HPV analysis on a cohort of 236 vulvar cancer patients in order to investigate whether or not this HPV status influences prognosis. And here you can see the results of our cohort study. Here you see the HPV positive group and in red the HPV negative group. And what we found was that HPV positive vulvar cancer patients have a lower recurrence rate compared to the HPV negative vulvar cancer patients. We also saw that the disease-specific survival was better for the HPV positive vulvar cancer patient group. A study published in 2017 has similar results. In this study, the authors performed a retrospective cohort study on 201 patients with vulvar cancer. And what they found was that HPV positive vulvar cancers had a better overall survival, a better disease-specific survival, and a better progression-free survival in univariate as well as in multivariable analysis. So I think we can state that the HPV positive vulvar cancers indeed have a better prognosis. Is it also possible to stratify into three molecular subtypes? And how can we establish this stratification in an easy manner? Next-generation sequencing for P53 mutation status is not widely accessible. And therefore, we performed a small concordance study to see what the concordance was between P53 mutation status based on next-generation sequencing and P53 immunohistochemistry. And we subdivided the immunohistochemical staining pattern into three different types of staining, a normal P53 expression with some expression of P53 in the cells, or an aberrant P53 expression, which could be either complete absent P53 expression or increased P53 expression. And what we found was that when we compared it with the NGS data, we found that the concordance of this staining patterns with the NGS data were substantial with a kappa of 0.72. So we used this knowledge to look again at our group, our cohort of 236 sulfur cancer patients, but now also subdivided the HPV-negative group into patients who had a normal P53 staining pattern and a group that had an aberrant P53 staining pattern. And although the Kaplan-Meier fishery suggests a difference, unfortunately, we were not able to refine P53 status as a different prognosticator within our cohort. Probably this was due to two small patient groups. Still, if you look at these results, you can say that there might be a third prognostic group of sulfur cancer patients. My successor, Dr. Portakas, extended our study in a larger group of sulfur cancer patients. She again looked at the concordance between P53 mutation status and P53 immunohistochemical staining patterns. But she did not subdivide it in three different types of staining patterns, but in six. Wild-type patterns were considered scattered positive staining or mid-epithelial positive P53 staining. Mutant patterns were defined as having basal overexpression, parabasal or diffuse overexpression, cytoplasmic overexpression, or again, the complete absent expression of P53. And as you can see, she found a high sensitivity and specificity for this concordance and an accuracy of these data of almost 97%. So again, she investigated also the subdivision into three different groups. And she included a larger group of sulfur cancer patients and collected a cohort of 420 sulfur cancer patients. They were subdivided into three molecular subgroups based on P16 and P53 immunohistochemistry. P16 positive patients were tested for the presence of high-risk HPV by HPV PCR. And in case of discordance, they were excluded from the analysis. HPV negative sulfur cancer were further subcategorized based on the P53 pattern immunohistochemical staining pattern that I showed you before. And here you see your results. The green line being the HPV positive sulfur cancers, the blue line the HPV negative P53 wild-type, and the red line the HPV negative P53 mutant sulfur cancers. And Dr. Korsgaas was able to identify three prognostic distinct sulfur cancer subtypes based upon this P16 and P53 immunohistochemistry. She saw that HPV positive sulfur cancers had the best clinical outcome, and that the group of patients with HPV that were HPV negative and P53 mutants have the highest risk for death and recurrence. So if we look again at the slide of the pathogenesis of sulfur cancer, we could state that especially the HPV-independent sulfur cancer group should be further classified based upon the P53 status into HPV negative P53 normal sulfur cancers and into HPV negative P53 aberrant sulfur cancers. What is interesting is that recently a different subset of HPV-independent precursors have been described, namely the differentiated exophytic full for intraepithelial lesions, the DEFLS, or endofulfur acanthosis with altered differentiation, the FATS. And these precursor lesions seem to be associated with the particular subset of the HPV negative a P53 wild-type full for cancers. So in summary, I think that based on the results I've shown you, we could say that full for cancer should be subdivided into HPV positive and HPV negative full for cancer at least. And I truly believe that this distinction is important. The WHO classification that was published in 2020 does describe that this differentiation for all full for cancer patients should be made. And maybe in the future, we can even subdivide it into three distinct molecular subtypes with a distinct clinical behavior based upon HPV status and P53 mutation status, which can be evaluated by P53 immunohistochemical staining. And I think we can state that the HPV positive full for cancers indeed have a better prognosis than the HPV negative full for cancers. So how can we trans use this knowledge into future clinical practice? Or how can we translate this translational research in full for cancer from bench to the clinic within the next decades? So I truly believe that in a few years, we will have different treatment strategies for HPV positive and HPV negative full for cancers. I truly believe that this distinction will make a difference for the patients. At this moment, establishing HPV status in all full for cancers can already ensure that clinicians will consider the natural history of these distinct diseases when they compose a treatment plan for the patient. You can say that the more aggressive nature of HPV independent tumors suggest that more radical surgery attaining greater surgical margins is indicated, as well as more frequent surveillance visits after primary treatment. The less aggressive behavior of the HPV associated or HPV positive tumors, combined with the fact that they occur more often in somewhat younger patients, suggest that less morbid and this vicarious surgery may be appropriate for these patients. Furthermore, it has been suggested that HPV positive full for cancer patients have a favorable response to radiation therapy, which is already established again in the head and neck cancers. I think in the future, we should also discuss about the treatment of the groins. Is it, for example, necessary if you cannot find the central nodes in HPV positive, in the groins in the HPV positive full for cancers to perform a full in quino-femoral lymphadenectomy? Of course, this needs to be investigated in prospective studies to see if we can establish oncological safety with less radical surgery in HPV positive full for cancer patients. And although we gained a lot of knowledge on the genetic background of full for cancer in the last decades, I think there's a need to continue full for cancer sequencing and ultimately, hopefully, sequencing the whole exome or whole genome in order to gain more knowledge on the pathogenesis especially of the possible thirds and molecular subtype of full for cancer. And of course, in the future, we should aim on the introduction of targeted therapy for full for cancer patients, especially for patients with high stage or recurrent disease. And thus far, there have been some publication on potential therapeutic agents, which target the most frequently encountered aberrant pathways involved in full for cancer pathogenesis. But further research is urgently needed before we can introduce this in daily practice. So I want to thank my colleagues from the Department of Gynecology and Pathology from the LUMC, Dr. Trietsch, Dr. Kortekaas, Dr. Van Koolgeest and Dr. Bosse, who were able to play their large role in my PhD and thank you for your attention. Well, thank you very much, Dr. Noy for this very interesting and excellent presentation, which I'm quite sure will raise a lot of questions, especially with respect to the clinical translation, which is really provocative. And so we will, after the next presentation, we will certainly come back to it. But thank you very much again. Our next presentation will be by Dr. Georgia Garganese from Rome University. In Rome, we do have a very active group with respect to clinical research in vulva cancer. And we are quite happy that Georgia is with us here today. And she will present on what is next after the groin's fee studies. Georgia, please go ahead. Good afternoon, everybody. I would like to thank you for the kind invitation, to thank also the Scientific Program Committee for the invitation. And I have nothing to disclose. Just, I would like to enter directly in the topic of the lecture. We all know that primary vulvar cancer frequently spread to local regional lymph nodes and that lymph node status is one of the most relevant prognostic factors. And currently, sentinel node procedure is considered as the standard of care instead of radical dissection when inguinal lymph nodes are preoperatively assessed as negative. But it is true only if some strict criteria are fulfilled. I mean, only when the tumor is unifocal, only when it is less than four centimeter and never subjected to previous surgery or to neoadjuvant treatments. Historically, this standard of care was established over past two decades by a series of study reporting robust data about safety, adequate detection rates, and about also the reduced morbidity of the sentinel node compared to inguinal femoral lymph node. Just to have an overview and starting points, I should mention that the groins one that is published on 2008 by Professor van der Zee and the other Dutch colleagues, it was the largest service published in those years performed on 623 groins. And the study concluded that sentinel node was a very safe procedure if it was limited to the criteria that I mentioned before. And in case of midline primary tumor site, only if a bilateral drainage of lymphocentrography was supplied and also with recommendation to use the 99 technician level radio tracer instead of blue dye. And the second key trial was the GOD 173 published in 2012 by Levenbach and the other colleagues from MD Anderson. It was performed on a series of 452 early stage vulvar cancer patients. And this study included the sentinel node biopsy always followed by a complete inguinal femoral lymphadenectomy finding a false rate of 2% in the tumors that measured from two to four centimeters, but it was significantly higher 7.4% in patients with tumors measuring more than four centimeters. So the conclusions were that it was safe under four centimeters. Moreover, a number of following studies that were associated with the groins one were published afterwards. One was about the favorable impact of sentinel node on the quality of life and following one showing a correlation between the increasing sites of sentinel node metastasis and the increased risk to find other metastasis in non sentinel nodes and also correlated with the corresponding worsening of disease specific survival. When we saw that it dropped down from 94 to 69% around the dimensional cutoff of two millimeters it was the cutoff. One, another study was about the undefined clinical significance and management of micrometastasis that means tumors less than two centimeter in the lymph node. And finally in 2016, the last study about the long-term follow-up reporting a 10 year local recurrence rate that was significantly higher for node positive patients of course, 45% compared to the negative one, 36 and the rate of isolated groin recurrence rate almost of 2.5% for sentinel node negative patients. So it was considered of course safe. And well, it is nice to report that in the same journal issue in which the updated follow-up was published. There was also an editorial, a prophetic editorial by Pedro Ramirez in the Levenbach underlined that there were a lot of relevant ongoing questions that today are mostly still under investigation. Just to list someone on them. First was that the need to standardize the preventive evaluation and the ideal imaging modality and also the rule of the PET-CT that in that moment was quite still undefined. Today is more clear. Another issue was the essential requirements for a surgeon's learning curve that is critical for the successful procedure. And another topic was the ideal tracer for mapping. Currently it regards the near infrared fluorescence guidance obtained by Indochannin green hybrid tracers that is a relevant topic. And also in the last two years the supermagnetic iron oxide nanoparticles that presently was introduced in the experimental ground. Well, following the timeline some of these major open questions were phased in these following studies that mainly aim to extend the criteria for sentinel node. It was the series of Gross-Napetz studies. And another line that was to try to avoid unnecessary lymphadenectomies even in case of positive sentinel node as it was the Groins-2 and the Groins-3 study that we'll see. So the real background from which we have to start is that a large number of node negative patients are unsuitable for the strict standard criteria and still undergo inguinal femoral lymphadenectomy. So they receive unnecessary radical procedures in the 70% of cases because they result node negative to the final histology without benefit and just bearing post-operative morbidity such as lymphadenema that significantly impairs the quality of life before an effort is needed to go beyond the current criteria. And addressing this question, the first step was signed by a prospective single center trial, the Gross-Napetz study published in 2017 by our Italian vulvar cancer team. The study aimed to verify the rule of sentinel node performed in a cohort of node negative patients, of course, but unfit for standard sentinel node criteria. That means with primary tumor larger than four centimeter or undergone incomplete diagnostic excision before a sentinel node or multifocal or with a contralateral or unilateral metastasis. We included also some local recurrences and patients after neoadjuvant treatment and previous radiotherapy. The second aim of this study was to address to another question that is whether a careful preparative imaging by ultrasound and PET-CT evaluation could improve the selection of node negative patients. And this is the flow chart of the study. During five years of the study, node negative patients were selected by ultrasound first and that was not suitable for sentinel node, underwent PET-CT to accurately exclude metastasis. And all of them received the standard sentinel node mapping using double tracers, that means radioactive tracer and blue dye being also preparatively studied with a lymphoscintigraphy and also a SPECT-CT. All of them received surgical sentinel node procedure, but always followed by the standard radical lymphadenectomy regardless of histological results of sentinel node. And the reference standard was of course the pathologic exam after lymphadenectomy. And a total of 73 groins were enrolled and in this series, no false negative sentinel node was found. And this was the first important result. Moreover, the performance of preparative imaging, ultrasound and PET-CT was remarkable. In fact, a negative predictive value was higher than 90% and we reported only four false negative results at the imaging. And in all cases, the metastasis was very small with a diameter ranging from 1.5 to six millimeter. So clearly near to the expected detection capability. And the key point was that all the metastatic lymph nodes missed at the preparative assessment by PET-CT were always reviewed by sentinel node exam, suggesting that the combination of PET-CT and sentinel node could provide near a 100% of negative predictive value. This is an anticipation of the results of the still unpublished update of GRASNAPET study that was obtained in an extended series of 111 groins. As you see in these extended series, we found one case of false negative sentinel node that means less than 1%. With the presence of only one metastasis in the non sentinel nodes. Anyone with a negative predictive value very, very high of 98% and always small sized metastasis in the sentinel nodes that was found positive. And third, an additional perspective trial that GRASNAPET2 is currently ongoing aiming to validate sentinel procedure in the same population, but the study design this time omits inguinal femoral lymphadenectomy in case of negative sentinel node. Therefore, if we assume that if a groin relapse occur within the first two years of follow-up, it should probably depend on the persistence of disease rather than a recurrence. The rate of specific local recurrence in this period has been considered as the measure of the sentinel node false negative rate. And currently the enrollment has been already completed. And we can present the preliminary analysis of these areas with the median follow-up of 15 months. We have to arrive to 24, of course. This is the distribution of the enrolled patient in all the categories and all the inclusion criterias with that 25% of population showing more than one selection criterion. And this is the floor chart. 80 patients enrolled in the three-year study, 122 groins eligible for analysis, excluding patients with drainage failure or those who refused then the delayed lymphadenectomy when the diagnosis was obtained on definitive histopathologic exam. And among these 122 groins, 88% had a negative sentinel node and only 15 were positive and underwent radical lymphadenectomy according to the design. Therefore, sentinel node detection was very high also in these series. Again, a relevant key point was the important contribution of imaging which adequately selected node negative patients. In fact, the rate of groins with metastatic sentinel node was very low, just 12% versus about 30% reported in the literature. And about 6% of the lymph nodes were positive. That means a very low number of unrecognized metastasis in the preparative imaging. The median metastasis diameter was four millimeter and in all positive cases except one, the other non-sentinel nodes were negative suggesting that at least potentially an additional number of lymphadenectomies could have been further spared. And as regards the groin space that was the major aim of the paper, the only case occurred in a 90 years old lady among the excluded patients. On the contrary, until now in the study group, no specific groin relapse occurred. So in total, we had 10 patients relapsed, but in other sites, not in the groin with the median time to relapse of 14 months and two among them died of disease. Therefore, these studies suggest that a careful preparative imaging may reduce the risk of misdiagnosed non-palpable large metastasis and the related least risk that a large volume metastasis in the sentinel node may skip the radio traces between either lymph nodes thus missing the real metastatic sentinel node with a false negative sentinel node. And these should be focused in the most crucial point of preoperative imaging. I mean, the small micrometastasis of course remain a challenge, but they are under the resolving power of any type of imaging. So, but certainly imaging can detect very well the non-palpable micrometastasis. And in our experience, ultrasound can be considered the most promising method for a first-level evaluation, although it is almost ignored by the NCCN guidelines. We can say that ESCO ESMO guidelines already suggest to employ the ultrasound with additional fine needle aspiration when it is appropriate, and the need to standardize methodology and to put an agreement about terms, definitions, measurements has been fully addressed by this relevant document. This is a consensus statement on lymph node ultrasound just released by the International Vulvar Tumor Analysis Group, the VITA group, that aims to supply and to share the basis for a standardized methodology for the next coming trials. Moreover, recently, we published the largest single-center study, the MorphoNUD study, where the experienced examiners evaluated preparatively a series of approximately 250 groins, analyzing 15 morphological and dimensional ultrasound parameters. All the study groins underwent surgical staging before the reference standard was pathology, and we found that all those ultrasound features considered as suspicious were observed more frequently in the metastatic groins in a statistically significant way, and that the negative predictive value of ultrasound in the most performing parameters was up to 95%, so very, very high. The real need is to get ultrasound reliable even when performed by less experienced examiners, otherwise it is not useful. Therefore, we realized a predictive model, the MorphoNUD model, based on artificial intelligence and machine learning technology, using a number of morphometric ultrasound that were respectively collected in a series of 230 groins. We evaluated preparatively and then subjected to surgery all these groins, and the machine was trained using deep learning analysis to learn how to predict lymph node status. I will not get into the details, but I can say that the model is going to be ready and it works very, very, very well with high performances before it would be our purpose to validate it prospectively, maybe in a multi-centre study. Moreover, PET-CT is another important tool. It is confirmed to be very reliable. This is a recent meta-analysis in a total number of 245 groins, and the special information is that negative predictive value is very high, 92%, and on the contrary, the positive predictive value is largely suboptimal, 70%. Therefore, it's like to say that if the PET is negative, we should be confident, but when it is positive, maybe we should interpret it with more caution. And the confirmation of these findings come out from another large single-centre study evaluating preparatively about 300 groins showing negative predictive value of 91%, so very, very reliable. And to dip this information into the clinical practice, there are some comments of Nicola Seide in this nice editorial that lists some situations where an additional preparative PET-CT could be useful to modulate surgical staging in node-negative patients. As you see in the first pillar, supporting the use of sentinel node procedure even for patients standardly unfit, and this is the results from GROSS-NAPAGE1. In the second pillar, avoiding standard inguinal femoral lymphadenectomy in case of midline tumours candidate to bilateral sentinel node biopsy, but with a missing drainage of a single side. And in the third pillar, in case of unilateral metastatic sentinel node, avoiding the unnecessary contralateral groin dissection. So going over, the other related relevant emerging question is, could inguinal lymphadenectomy still be avoided in selected cases with metastatic sentinel node? And this is the topic of these two large international prospective multi-centre studies. The first one is growing to investigate whether inguinal femoral radiotherapy could be a safe alternative to the radial lymphadenectomy in case of metastatic sentinel lymph node. According to this study, all patients positive at sentinel node received a standard dose of 50 grays. And the primary endpoint was the groin recurrence in the first two years, as I said before why. And at the interim analysis at five years, they found an exceeding rate of isolated groin recurrences in the subgroup with metastasis larger than two millimetres or with extra capsular spread. The four protocol was amended and these subgroup of patients was addressed to standard lymphadenectomy while the group with small metastasis continued to receive radiotherapy according to the design. And in these micrometastatic subgroups, recurrences rate at two years was 1.6, very low. So it could be interesting. And the micrometastatic subgroup had a recurrence rate of almost 7% when standardly treated by surgery and 22% if radical surgery was submitted in favour of radiotherapy. Therefore, the study concluded that patients that are suitable for standard sentinel node biopsy in case of small metastasis could be safely addressed to radiotherapy with an improved treatment related morbidity. Moreover, a last final design of these series of big groins studies is the Groins 3 that is now just ongoing trial. The aim of this trial is to investigate whether in case of large metastasis, larger than two millimetres, lymphadenectomy can be safely omitted, increasing the efficacy of radiotherapy treatment, adding chemotherapy or giving a higher dose. And of course, we are really interested to know the results of this important trial. The final question is if we could completely omit in selected low risk cases, the sentinel node biopsy. The question is almost completely unaddressed in the present literature. There are no predictors identified, for example, among the primary tumour clinical pathology molecular features or clinical features. Therefore, it is a long way to be explored, but we need to understand when it is safe to omit surgery, for example, for patients with low risk disease, old age and high comorbidities or otherwise in the median lesions that have a unilateral drainage or when a monolateral node positive in the lateral lesions have no contralateral drainage. Okay, so this is an open question that we are going to discuss. And just to summarise some messages to take home, I should say that if you stay into the recommended criteria, sentinel node is safe and a very high negative predictive value about the status of non-sentinel lymph nodes. Second point is that imaging, meaning ultrasound and PET CT performed by experienced examiners and in referral centres could allow a reliable preoperative selection of clinically node negative patients that could be expected at most to have just small metastasis and therefore safely support both an extended use of sentinel node beyond the current strict criteria and maybe omission of lymphadenectomy even in case of non-small sentinel node metastasis testology. And the last point is that radiotherapy is a promising alternative to radical surgery in case of small metastatic sentinel nodes and maybe chemoradiotherapy could potentially allow to spare lymph node dissection even for larger metastasis. Last, the last remind that for me is mandatory is to remember everybody that all referrals sent should collaborate in institutional network just to realise large comprehensive trials in useful study times interval. Thank you for your attention and I thank you again for the invitation. Thank you, Georgia, for this very nice presentation and you should be commended for the extensive clinical research that you are doing this very rare tumour, you and your co-workers and I think that is excellent. And with that, I'm now passing over to Anuja who will introduce the next presenter. Anuja. Thank you, Ada. And moving right along, the next presenter is Dr. Dornhofer from Germany who will be presenting on vulvar reconstruction by plastic surgery after treatment for primary and recurrent vulvar cancer. Dr. Dornhofer, please go ahead. Okay, great. So, thank you very much for the invitation and for the opportunity to talk on this, I guess, really important topic of vulvar reconstruction after treatment of vulvar cancer. I have nothing to disclose. We all know vulvar cancer rates are rising and particularly in young women. So, particularly also in young women, reconstruction might be even more important than in the very old women. And unfortunately, these are results of the standard treatment that we still see as current treatment has no focus so far on reconstruction. And also, this is one of the examples. And when I show these slides, I'm always told, well, Nadja, this is samples from the old times. Nowadays, everybody's doing reconstruction. But this is a patient that I saw actually two weeks ago and she only had severe dysplasia. She didn't even have a vulvar cancer. So, she had a vulvectomy and a second vulvectomy because the margins were not clear. So, that is why I think still an important focus to put on vulvar reconstruction. So, after standard treatment, Sven, thanks to your great study, we know that heavy disturbance of body image applies for more than 50% of patients. And of course, also heavy disturbance of aesthetic and sensory function also in more than 50% of the patients. So, what do I want to talk today? First, I want to show that, of course, in very small cancers or very small vulvar defect after surgery, you not always have to do plastic reconstruction. There are also strategies to overcome these wounds, for example, by primary wound closure. I will show one or two examples that are somehow acceptable. And also by primary-secondary wound healing, meaning you keep the wound open and you do not perform a primary closure. And also the secondary healing can give great results in small defects. But as soon as we have a little bit smaller defects, I think we should all consider anatomical reconstruction. And I will show the most important flaps. There are plenty of possibilities. But we have actually, in our experience, we have two random skin flaps that are easy to perform, two extra pattern flaps that are easy to perform, and also two distant flaps that are easy to perform. Because, for example, in a recurrence, when the perineum is irradiated, you cannot use local flaps like random or extra pattern flaps, then you need distant flaps because you need to bring not irradiated tissue in the wound. So first, strategies without anatomical reconstruction. So I said already primary wound closure. Of course, there are cases with small cancers like this one in an older patient, very severe illnesses, and she did not want to have anything done that would make the surgery any longer. So we decided to do a primary closure. And you can see this is our anterior vulva field resection that's necessary for this kind of cancer. And then here we did a primary closure. This is the result after what it looks like after two to three weeks. And this is after healing. And I guess for this patient, and she didn't want to, and she was very old and ill, this is an acceptable result, because at least the vaginal orifice is wide enough to do a regular gynecologic exams. But I guess everybody would agree for a young patient or a patient that has still intercourse, this is probably not a very nice result. Here, a patient with basal luma. So of course, in these cases, you can also do a wide excision with a primary closure that you can see here after three months or after six months, you can have quite an acceptable result. So this is another case where we did a primary closure. You see a very small cancer between clitoris and urethra. And we performed an inner anterior vulva field resection and did a primary closure. This is the picture after six months. From the outside, you can barely see that there was a surgery. And also the introitus is wide enough. So penetration is possible. And also here, I guess the cosmetic and aesthetic result and also the functional result is acceptable, even though we did not perform anatomic reconstruction. So the second possibility to avoid anatomical reconstruction is a primary-secondary wound healing. What do I mean with this? This is a small 1A cancer with surrounding severe dysplasia. And we did posterior partial vulva field resection. And this was the wound after the surgery. And we did not do anything to this wound. We could have done limbal flaps or we could have sutured it primarily. But we left it open. And this is the wound after two to three weeks. And finally, after three months, this is the final result. And I guess here again, there you can barely see that anything was done. And also here, the area where the tumor was and where the secondary wound healing was is healed very well. And she has no deficiencies in function of the vagina. And it's soft and elastic tissue. And also here, a small cancer again between clitoris and urethra. We did here an inner. Unfortunately, I have no pictures from the OR. So we did an inner lateral vulva field resection. And this is the result after six months. Here you can see the area that was left open for secondary wound healing. And I guess if you compare this picture with this picture, it's quite a good functional and aesthetic result, even without anatomic reconstruction. But of course, very often we see bigger tumors that need more extended resection. And after this kind of resection, we think you always should do anatomic reconstruction. What's the aim of the anatomic reconstruction? We want to restore form and function of the vulva. We want to restore the labial folds with two adequately sized sensitive skin folds in sagittal symmetry. The orifice should be sufficiently wide and elastic so that there's no disturbance in function of the vagina and also not in urinating and defecation. You should, of course, restorate the perineum, which is an important aesthetic effect of the vulva. And you can restore the anterior commissure with clitoral protrusion. Of course, if we have to remove the glands of the clitoris, we still have the corporis and the crura. So sensitivity is still there, at least after three to six months. What are the limitations of our anatomic reconstruction? Of course, it's usually not possible to reestablish the priputium, the glands, the frenula of the clitoris and the labia minora. Also, the gulbi cavernosae, if you need to resect them, are not restorable. And after radiation, you always have to have to bear in mind that reconstructive possibilities are limited because then you cannot use local flaps because you would take the flap, the flap donor side would be within the radiated tissue, which means that all the stem cells are not there anymore that we need for wound healing. So if a patient had radiation of the perineum in the past, then we have to take distant flaps that I will show you later, of course. And of course, the area of the tissue you take the flap from should be free of residual or occult disease. And of course, the advantages of reconstruction must outweigh the risks. So this is an algorithm that we propose. So we classify the vulva defect and a partial defect, total defect, or an extended defect that on the right here is most of the time is the case if you have recurrent disease. And then for all kind of these defects, we have several flaps that are suitable. And I will talk about the red highlighted flaps today, the pupillary VY flap, the limber flap the labial flap and the pudendal thigh flap as regional or local flaps and the gracilis flap and the gluteal thigh flap as a distant flap for example, for patients after irradiation. So this is the pupillary VY advancement flap. I will show all these flaps in detail. This is a random flap as well as the limber flap, which is also a random flap. You can use these for anterior defects and this flap you can use for posterior defects. As I said, it's random skin flaps. And then we have two axial pattern flaps that are easy to use. It's the labial flap, which can be either anterior or posterior. And we have the lotus petal or pudendal thigh flap that you can use in this way also. This is an axial pattern flap. So first to the random skin flaps. What does it mean it's a random skin flap? Random skin flaps lack a specific named vessel. So they are diffused from perforator arteries that are located near the anatomic base of the flap. So this is the area and you can just move it from one side to the other side. And also here, the vessels go within the tissue. So there is no problem regarding perfusion of these flaps. And the first random skin flap I want to show is the Limberg flap, which we use for posterior defects. And I show you here. So this is the small cancer and this is the area that will be resected. So when you want to perform a Limberg flap, it's always important that you use a diamond shape of 120 degree angle here and a 60 degree angle here. So in this case, you make two diamond shapes next to each other for two Limberg flaps. Then you take the short diameter of this diamond and extend it for double. This is here. This is going to be a new tip of the diamond. And then you just take a parallel incision to the margin of your defect. So here is your diamond shape. This is your short diameter. You prolong this short diameter and parallel it. And then you have the area that you can rotate. So this is our resection area. Now you dissect the donor side and you close the donor side. And that's the result after three months. So after six to 12 months, when the wounds are healed completely, you won't even see these sutures here. So very important for this flap is that you do the calculations you need and the drawings or the planning of the flap before you do your excision. And then you have, as I said, the diamond shape. And sometimes you need two diamond shapes to get a nice slimmer flap. And these flaps are really easy to perform and we barely have severe complications. So the second random skin flap is the pupolabial V-Y advancement flap, which we can easily use for anterior defects. Here's an example. So this is our defect after vulvar cancer. We did an anterior vulvar field resection, and this is the design of the flap. So what is important in the flap is, so this is your basis. So the basis of the flap. And first you have to measure how wide you can make the base of this flap. And then you can calculate the length of the flap. So B is two times A. So the flap can be double of the length of the flap. Can be the double of the basis of the flap. So this is two times A. And then you prepare everything. So you lift the pedicles of the flap and you do your preparation at the manspubus. And then you see that the tissue nicely slides downwards, which then creates the Y. And then we do anchorage sutures so that we can design the flap and the important here is that you close the wounds from the top to the bottom so that you have enough space here, which I will show you later for the intro. So this is the tip of the flaps. And very often you have here the problem that if you keep them, you have tip necrosis, necrosis of the flap tip. So if you have sufficient tissue to close your defect, you can, or it's a good idea to resect these last millimeters or last 10 millimeters of your flap to be safe that you have no tip necrosis there. And then you rotate the flap inside and suture it to the vaginal orifice. And then now you have your flap completely finished. Very important is once you do these reconstruction, it should be done by having a specular inside so that you have, you can be sure that the intruitus is wide enough for intercourse afterwards. And that is the same without the specular. And that's a picture after six months. And I guess for a young patient, that's quite a very good cosmetic result. And as I said, this flap is really easy to perform. So now for the axial pattern flaps. There we have the labial flaps and the podendal thigh flaps that I will show you. The axial pattern flap is not like the random flap perfused by random vessels. It rather has a direct cutaneous artery or vein into its base. So you have the veins that, and the arteries that supply your vessel and you move like a peninsular or insular flap. Flap also these, sorry, these vessels, which can then easily perfume your flap. So this is quite a big vulva cancer between again, clitoris and urethra. We performed total vulva field resection, which you can see here. And then we created two labial flaps here and here, which are perfused here. And here through the posterior labial artery. And this is after closure of all our donor sites and the area of the vulva field resection. And that's the result after six months. And I guess again, of course, the vulva is not looking as it was before, but you have a two longitudinal folds. You have a sagittal symmetry and you have an atritis which is wide enough for either intervals or gynecologic examinations. So the last axial pattern flap is the pudendal thigh flap and that I will show you. And here you have, again, this is a recurrence. And as you can easily see here, you have your cancer or the cancer or the recurrent cancer. We did a total vulva field resection. With the results you can see here. And then you can create either here or here or here, depending on which tissue you want to use. You can create your thigh flap, which is then perfused by the peroneal terminal branches of the internal pudendal artery. And again, you can rotate these flaps easily in your defect, like here. Then you have here the donor site that needs to be closed and you have the flaps moved in your resected area. You suture everything together. And after six months, oh, and again, before I forgot that, before I forget that, again, it's important to do the suturing with a speculum. So you are sure that the introitus is wide enough. And this is the result after six months. So these all are local flaps that you can easily use if the patient is not irradiated in that area before. Once the patient is irradiated, you cannot use that irradiated tissue as flap donor site. So then you need to use distant flaps, for example, the gluteal thigh flap, which is shown here. Here you can see the cancer, which was treated before with vulvectomy and adjuvant radiation. So we cannot use any of this tissue that was in the radiation field. So we have, as I said, to use the distant flaps. So this is how you can design. So you see the resection area is quite big and you need also big flaps, of course, to restore that. And this is the result after using this kind of flap. And of course, after recurrent cancer and after irradiation, your aesthetic goals are different. So the primary focus then is to get these wounds closed anyway, and I guess aesthetic aspects are secondary in these cases. And the second distant flap that is easy to perform and I want to show is the musculoskeletal flap that you can see here. And this is also a patient with a recurrence. And here again, you can use these flaps particularly for lateral defects, or if you need to take it from both sides, then of course, that's also possible. It's also quite an easy flap to use. But of course, this is not as nice to use as the local flaps. So it should be reserved for really big cancers or for patients that got irradiated before and where you need tissue as donor tissue from not irradiated areas. So what's about the complications? So of course, due to the proximity to the anus and the fact that we never have a sterile area in the vulva, we have also wound infections from 10 to 50%, but we see less wound infections in patients with anatomic reconstruction compared to patients without anatomic reconstruction. Then of course, the wound dehiscence, the problem, very rarely, it's also the donor side that has a dehiscence, but sometimes also the flap. The risk factor for this, of course, is wound infection, which is the most important risk factor. Once the infection is gone and the wound is healing, it takes, let's say, two to three months for secondary healing and the wound is closed. And very often we see that even if we have secondary wound healing, the cosmetic result is not really impaired. Flap necrosis is a very rare complication. Most of the time, if at all, it's only the tip that gets a necrosis and the total flap necrosis is really rare with less than 2%. So contraindications are, of course, very obese patients, diabetes, smoking, peripheral vascular disease, or venous insufficiency. If a patient has several of these risk factors, you should always check whether this is a good candidate for anatomical reconstruction. So to summarize, I wanted to show two strategies to restore the vulva without anatomical reconstruction. Then I showed you the most important flaps, at least in our experience, that we can use to reconstruct the vulva. These are the four local flaps that we like to use. And hopefully, if we all are trained in these flaps, we can make out of the results in the first row the results in the second row. Thank you very much. Thank you. Thank you so much for a lovely talk. It was excellent presentation. And for everybody who's just tuning in, this is the master session dedicated to vulvar cancer. And thank you for joining us. Next, we have Dr. Gaffney from the US who will present on the role of adjuvant radiation therapy. David, please go ahead. So good afternoon. And depending on where you are, good morning. It's really a great pleasure to be part of this fantastic panel. I'll be discussing a number of important things in vulvar cancer. I just wanna remind people, this is quite a rare disease, and it's a significant challenge, I think, to manage these patients. And for that reason, it's also very interesting. Okay, this was a fantastic manuscript summary guideline paper out of our colleagues from Europe. And they made a number of salient points, which I think were quite remarkable. And that is adjuvant radiotherapy should start as soon as possible, preferably within six weeks. Additionally, there is no consensus for the threshold of pathologic margin distance below which adjuvant radiotherapy should be advised. Post-operative radiotherapy to the groin is recommended for cases with more than one lymph node and or presence of ECE or extra capsular node involvement. Adjuvant radiotherapy for groin nodes should include an upper limit at the level of the bifurcation of the common iliac artery. And based on evidence from other squamous cell cancers, such as cervical, head, neck, and anal cancer, the addition of concomitant radiosensitizing chemo should be considered. So how do we do vulvar radiotherapy correctly? This is a manuscript out of MD Anderson that makes a few points in this regard. This was a Seer Medicare study. They had 306 patients, 69% received radiotherapy. The median age was 78. Three metrics were associated with improved outcomes. Completion of greater than 20 fractions, treatment duration less than eight weeks, and less than one week of intratreatment break. Patients who achieved those metrics demonstrated better disease outcomes compared with surgery alone. And only 51% of patients who received radiotherapy achieved all of those benchmarks. So let's talk about margin status. This is, I think, a fascinating topic in vulvar cancer, and there's some wonderful new data. So what we do know is there's a high local recurrence rate. Margin status has been populated, postulated, as well as DVIN and lichen sclerosis may also play a role. According to NCCN, surgical margins should be one centimeter. Recent studies question the traditional eight millimeters and smaller margins may be acceptable. For close margins, observations may be reasonable. Reexcision should be considered for a positive margin. Radiotherapy is another alternative. Survival difference between surgery and radiotherapy is not clear. Positive margins involve that urethra, anus, or vagina may not be resectable without significantly impacting quality of life. And reexcision may not be beneficial in patients with METs to the inguinal lymph nodes that require radiotherapy plus minus chemo after surgery. So the NCCN guidelines indicate for patients with positive margins, reexcision would be the standard if possible. If not, adjuvant external being would be the traditional plan. So perhaps one of the more cited papers is the HEAPS article from 1990. This was a single institution retrospective review from UCLA. They had 135 patients. 91 patients had a margin greater than or equal to eight millimeters and none had a local recurrence. 44 had a margin less than eight millimeters and 21 had a local recurrence, giving a highly significant P-value. And they concluded that surgical margin is the most powerful predictor of local vulvar recurrence. And that dominated the field for several decades, I would say, until this Sentinel paper came out in 2019 by our colleagues from the Netherlands. From two Dutch centers, they had 287 patients with mature follow-up, 80 months, and the actuarial local recurrence rate at 10 years was moderately high, 42.5%. Pathologic tumor-free margin distance did not influence the risk of local recurrence. And multivariate analysis showed a higher local recurrence in patients with DVIN and lichen sclerosis in the margin. In patients with DVIN in the margin, there's also a significant hazard ratio and advanced stage. So what the authors from the Netherlands observed, if DVIN was in the margin, again, they saw quite a very high recurrence rate. If DVIN was adjacent to tumor, there still was a substantial local recurrence rate, but markedly less. The panel on the right in the green shows both lichen sclerosis and DVIN. In the yellow, we see DVIN alone. In the purple, lichen sclerosis. In the blue, none. And in the red is H-cyl. This was confirmed by the Franco Gein Group that performed a multi-center review of 112 patients. They also looked at margin status. What they observed is in red, as you can see in this curve, are patients who had margin distance less than three millimeters. In black was three to eight millimeters, and in green was greater than eight millimeters. Again, not significant. So let's discuss the controversy of one versus two lymph nodes. This has been an ongoing controversy for a long time, and I think it's fun to explore. So the NCCN weighs in on this, and that is if tumor deposits in the sentinel lymph node are small, external being plus or minus chemotherapy is recommended. For larger deposits in the sentinel lymph node greater than two millimeters, inguinal femoral lymphadenectomy is preferred. So this was a remarkable study performed by one of our moderators, Dr. Manar, the AguaCare study. They confirmed that adjuvant therapy impacted progression-free survival. However, in their hands of a large number of patients, it did not impact overall survival. When they looked at the node-positive patients by the number of positive lymph nodes, those patients with a single positive lymph node did not appear to benefit from adjuvant therapy, whereas patients with two or more lymph nodes did appear to benefit from adjuvant treatment. So I've listed the studies that are supportive for no radiotherapy in a single positive lymph node, and that includes this study, the HOLMSLEY trial. And you can see here patients who received radiotherapy compared to the patients that received pelvic lymph node dissection. In the updated results of this manuscript published in 2009 by Charles Kunos, those patients that had a single positive lymph node showed no difference. So this is, again, is a study that shows no benefit for radiotherapy to the single positive lymph nodes. However, those patients that had more than a single positive lymph node appeared to benefit from radiotherapy. So the next studies are supportive for radiotherapy in the case of a positive lymph node. This was a SEER study performed by a number of colleagues, 694 patients. They found that a survival benefit persisted in women with just one and two positive lymph nodes and concluded that all node-positive patients should receive adjuvant radiation, including those with one positive lymph node. This study is a second study supporting radiotherapy in those with a single positive lymph node. This is an NCDB database study of nearly 2,800 patients. On multivariate analysis, radiotherapy yielded a survival advantage for women with one positive node and two or more positive nodes. Chemotherapy yielded an incremental improvement in survival for women with two or more positive lymph nodes, but not for those with a single positive lymph node. Additionally, this is a contribution, again, from the Franco Gein Group, and this is a supportive for radiotherapy in a single positive lymph node. They had 176 women with at least one positive lymph node. There was no significant difference for overall survival rates with one extracapsular versus one intracapsular lymph node metastasis or with two lymph nodes. For intracapsular metastasis, LVSI was an independent predictive factor for relapse-free survival. And adjuvant inguinal femoral radiotherapy was a positive independent factor associated with relapse-free survival. So irrespective of the number of affected lymph nodes, radiotherapy should be considered, especially in the case of LVSI. And the data is shown in the panel on the right, indicating that for patients with lymph vascular space invasion, they appeared to benefit from GOIN radiotherapy compared to those with LVSI that did not have GOIN radiotherapy. Okay, so let's talk about recurrent disease and a few other considerations as well. So the NCCN guidelines have these branched decision point trees. One of the major differences, of course, is whether patients had received previous radiotherapy. If they had, patients typically proceed to radical surgery. If not, and they're resectable, resection is typically preferred. Otherwise, external being plus or minus chemo, and then the branch points continue. So what does the NCCN guidelines indicate as best practices for radiotherapy? Treatments should be daily. Doses range from 45 to 50 gray and 25 to 28 fractions for adjuvant radiotherapy, and 59.4 gray to 64.8 gray and 33 to 36 total fractions, typically delivered at 1.8 gray per day. For bulky disease, one may consider boosting up to 70 gray. Of course, for ECE, the dose is higher as we know. So what about the role for chemotherapy and what are the data? So this is an NCDB study looking at 1,800 patients from our colleagues from Pittsburgh. Patients were treated with surgery and radiotherapy. 26% received adjuvant chemo and 76% had one to three lymph nodes. On multivariate analysis, the addition of chemotherapy resulted in a 38% reduction in the risk of death. And you can see that in the curves here with the red curve showing no chemotherapy. So this is a second paper showing similar results again from the same database from the NCDB. This is a publication from colleagues from Washington University. They had 1,352 patients, median dose was 59.4 gray and five-year overall survival was significantly higher in the chemo radiotherapy group versus the radiotherapy group, 50% versus 27%. So what about groin swelling or lymphedema? These data are a little bit not entirely appropriate for a talk on vulvar cancer because in the leg study as presented by Rich Barakat, GOG 244, the majority of these patients were treated for cervical or endometrial cancer. A vast minority of patients had vulvar cancer. In their study, they did not see that radiotherapy caused an incremental increase in lymphedema compared to surgery. So what have other data shown? This is a meta-analysis about the incidence of lower limb lymphedema after vulvar cancer. They had 27 studies, 2,500 women. Incidence was 29% overall and 17% in seven studies which were prospective cohort studies. Lymphedema was increased five-fold in inguinal femoral lymph node dissection compared to sentinel lymph node and radiation was a risk factor in one study. And of course, this is an important quality of life issue. As discussed quite brilliantly by our first speaker, HPV is a marked prognostic factor. These are the data from McAlpine et al. And there have been a meta-analysis which again shows the same thing. These are eight additional studies. The hazard ratio for overall survival was 0.64. This is almost identical to the hazard ratio which was shown earlier again by our first speaker in head and neck cancer. So I think this is quite a provocative data and something that we need to pay attention to. Can radiotherapy sterilize gross inguinal nodal disease? This is a small study from MD Anderson. The median diameter of the groin nodes was 2.5 centimeters. These patients had advanced disease. 48% had positive pelvic lymph nodes. The median dose was 60 gray. Three-year actuarial vulvar, groin and distant recurrence rates were 24, 17% and 30% prospectively. So at three years, 83% of patients did not suffer a groin recurrence. So what's the future in vulvar cancer in terms of radiotherapy? Proton beam may reduce side effects. Importantly, with proton beam, you don't have exit dose. So that may permit us to spare certain structures. And what about the role of surgery in markedly advanced vulvar cancer? What's the best therapy? This was an NCDB study out of Duke University looking at 2000 patients. Primary radiotherapy and chemotherapy in their hands was associated with compromised overall survival overall compared with preoperative radiotherapy plus surgery. However, when they looked at patients that received a significant dose, that is 55 gray or more, overall survival was not significantly different from radiotherapy and chemotherapy plus surgery. And they concluded that greater than 55 gray and concurrent chemo non-operative approaches had comparable survival compared with preoperative chemo radiotherapy and surgery. With that, thank you very much. And I'll look forward to having a discussion later. Thank you again. Thank you, David. That was a wonderful presentation. And now I'm gonna pass, and of course I'm gonna turn my video on, which won't turn on. And now I'm gonna pass the moderating duties to Dr. Mayer. I'm sorry about that. Thanks, Anusha. So what a great session. I'm really honored to be part of this. And I already now thank all the presenters for their really great presentations. And also the audience. We just learned that hundreds of international participants are now in the session here. And there already have been quite a few questions addressed through the website, but I just want to remind you at this point that the lines are still open to address your questions. And right after Dr. Hervé's presentation, which is always on time, I know her very well. And so we will have enough minutes to discuss all your questions and ask anything you would like to discuss about vulvar cancer, because we want to cover all the different aspects. But now, Lynn, it's time for your presentation. And we are glad to learn some updates about how to treat distant recurrence, what's new about medical treatment options, and where the silver lining on the horizon might be. Yes, thank you very much for the invitation to give this talk on medical treatment and distant recurrence of vulvar cancer. And actually the first thing I did when preparing for this talk was putting a question mark to the title, because I'm not quite sure if I see the silver lining already, but I would like to go through this with you all together. Just for a short background, you know that about 30% of all patients initially present with locally advanced disease in stages three and four. And those have a very high risk for recurrence and survival rate for those patients which develop recurrence and are not surgical, that are not surgical resectable is very low with only 30% one year survival rate. So we try to look at distant metastasis and vulvar cancer isolated. That's very difficult because we don't have hardly any data. And there are some unicentric cohorts and they describe a prevalence of about five to 8% of distant metastasis and vulvar cancer. And what's interesting is that there's a relatively short time described between the first diagnosis of vulvar cancer and the first occurrence of distant metastasis of only around one year. And then the median survival from the first diagnosis of distant metastasis is very poor with only 5.6 months described in serious from Hamburg. And you see here the distribution of or the localizations of metastasis and vulvar cancer described in the cohort of nearly 400 patients. And you see that most often metastasis to the lungs is reported and then very closely followed by liver, bone, skin and lymph nodes, distant lymph nodes. And the prognosis of these different sites of metastasis is almost the same except patients with isolated bone metastasis. They seem to have a little better prognosis but you always have to keep in mind that these are very, very small numbers. So earlier in the session, you heard a lot from Dr. Noy's excellent talk about potential future options. But now I have to confront you with today's reality. What are the current options in metastatic diseases in metastatic disease and vulvar cancer? And I want to take you through chemotherapeutic options and then the data we have on targeted therapies that we have collected so far. So if we look at chemotherapy, there has been a recent publication from Italy looking at chemotherapy in vulvar cancer. And this is a summary of studies with more than 10 patients receiving chemotherapy for recurrent or metastatic vulvar cancer. And this is already the pitfall. We hardly have any have cohorts just looking as metastatic disease but it's always these mixed cohort with locally recurrent, not resectable vulvar cancer which is biologically often quite different. So if you look at these studies, you see, of course, as expected, very small numbers. And what you also see that there's a wide variation of response rates reported to the different chemotherapeutic schemes from zero response to 60 response, to 60% response rate. And you see, as expected, very limited prognosis. There's one study that might pop up to your, to you regarding the prognosis reported with a PFS of 10 months and OS reported of 19 months which is compared to the other studies much better. So I wanted to show you this study in a little more detail. This is a phase two study which was published in 2009 with 16 patients and with only local regional recurrence of vulvar cancer after vulvectomy and lymphadenectomy and radiotherapy. And all these patients were chemo-naive and they all received a combination from cisplatinum and venoral bin and overall response rate of 40% was observed and a medium PFS of 10 months and OS of 19 months with the expected toxicities. And you now already see that this is not the patient we're normally talking about because we hardly ever see these patients because most of the patients are treated for primary ease with chemo-radiation already. So we hardly ever see chemo-naive patients with metastasized disease and cannot translate these results into the current clinical situation. So what are prospective studies including patients with distant metastasis? And there we have only two prospective studies which have very disappointing results actually. We have a study exploring a paclitaxel on a three-weekly scheme with an overall response rate of 14% in eight patients with metastasized vulvar cancer. And then we have a trial from Hanna et al exploring weekly paclitaxel and chemo-platinum and observing no objective response. So this is all we have in metastasized disease. So what do we actually do with our patients because we treat them anyway? And what we do is we treat them like other squamous cell cancers. We treat them like head and neck cancer. We treat them like anal cancer. We treat them like cervical cancer. And as most of us are gynecologists, we tend to treat them like cervical cancer because we know how the treatment works. As you know, the standard first-line treatment in cervical cancer is the combination of cisplatin and paclitaxel. And some of us even use the combination with bevacizumab because we can use it. For example, in Germany, it's usually reimbursed by health insurance. So we use it, but we don't really use it because we know it's the best choice, but we don't have any other choices or we don't know enough to give the patient other choices. And I try to explore other possibilities with you now. So the question is, are there better combination partners using for cisplatin, maybe five of you, like we use it in anal cancer, for example, or is there better maintenance treatment or even using maintenance anyway when not using bevacizumab? And that leads over to the data we have on targeted therapies in vulvar cancer. And this includes data on immune therapy we have collected over the last years. So if you think about what you heard earlier from Dr. Noy, there have been identified multiple potentially drug-able targets in vulvar cancer. Nevertheless, there is only clinical data for two pathways x-rays and this is the EGFR targeting and more and more for immune therapy in vulvar cancer. And these are the pathways I want to show you the data we have. So for the first targeting strategy, targeting the EGFR pathway, we have a phase two study already published in 2012, which included 24 patients with metastasized or recurrent vulvar cancer. They were treated with elogenib orally and the treatment showed quite an impressive response rate in the metastasized disease with nearly 60% of patients responding to the treatment. However, the medium PFS in this cohort was again disappointing with only a 3.2 month PFS and quite a toxicity, which is of course important in this frail patient cohort. And the authors couldn't really identify any biomarkers predictive for therapeutic response. And that's why the next study is very interesting because from other cancers, we know that activating EGFR mutations are used to predict response to EGFR inhibitors, for example, lung cancer. And this is a Chinese study published in 2017 of 13 patients with recurrent metastatic or persistent vulvar cancer. They were also all treated with oral EGFR inhibitor and the group looked for activating EGFR mutations in the tumor tissue of these and found quite a high mutation rate of 30% in these patients. And what they could also demonstrate is that the response rate, the disease control rate and also the overall survival rate was higher in patients with activating EGFR mutations getting the treatment. So this might be something that could direct treatment in the future. So if we look at the other pathway, the immunotherapy, we have gathered quite a lot of data during the last years, but still the cohorts for vulvar cancer are pretty small. The first I want to show you the data on potentially predictive markers in vulvar cancer. The first one is PD-L1 expression. And we know that a substantial proportion of vulvar cancers overexpress PD-L1. There's a recent publication showing a prevalence of a CPS greater than one in 86% of vulvar carcinomas. And then another publication from Munich showing a CPS score greater than 10 in over 60% of primary tumors. But you have to keep in mind, these are primary tumors and may not reflect the metastatic situation. And what is very important is that more and more groups could show that the expression status is independent of HPV status, which was not clear at first. There is data from the Keynote 158 study, which was a phase two basket study on pembrolizumab monotherapy in patients with rare cancers. And there is quite a big cohort of vulvar cancers with 71 patients. And what they could show is that the tumor mutational burden was a good predictor for therapeutic response in vulvar cancer. There were 17 patients showing high mutational burden and they had a much better response than patients with low tumor mutational burden who only responded in 3.4%. So if we look at the first clinic data we have on checkpoint inhibition and vulvar cancer, this comes from the Keynote 28 study. In this also basket study, in this study patients were treated with pembrolizumab monotherapy and there were altogether 18 patients with advanced vulvar cancer. And what you see here is that vulvar cancer is really last on the list with everything. You see very disappointing results with overall response rates of only 6%, medium PFS of three months, median OS of 3.8 months, which is of course also again restricted by the small numbers. A little more positive results come from the checkmate studies, but here the cohort with vulvar and vaginal cancer was much smaller with only five patients. There were only three patients with vulvar cancer, but here we saw 80% disease control rate and overall response rate of 20% with one partial response in vulvar cancer for nivolumab monotherapy. So what can we make out of this? In the end, right now we only see limited activity in vulvar cancer for checkpoint inhibition at this point. So the question is why doesn't it work? So I think it's mainly like in the other cancers we have that we don't know how to select patients for treatment. The second question is what can we do differently? And I think things will change anyway because all the studies right now running for cervical cancer with integration of checkpoint inhibition and earlier therapeutic phase will change the treatment in vulvar cancer as well because we will adopt results for vulvar cancer. And the question right now for vulvar cancer is how can we enhance efficacy of immune checkpoint inhibition at this point in second line treatment where we use it often on an individual basis in vulvar cancer. So there is a very interesting, there are several interesting combinations that you all know, like combining checkpoint inhibitors, et cetera, but there's especially one combination that is very interesting, which you all know from endometrial cancer, which is the combination of pembrolizumab and lanbatinib, the multithyrosine kinase inhibitor. And here you see the results for the head and neck cancer cohort, which as Dr. Noy already said, biologically quite similar to vulvar cancer. And you see these very impressive results for head and neck cancer, advanced head and neck cancer with an overall response rate of over 40% of these patients and a benefit rate of nearly all patients treated in this study. So that's why we decided to put up a study within the AGO study group, which will be hopefully launched at the beginning of next year. It's a single arm phase two multicenter study for advanced vulvar cancer or metastasized vulvar cancer. These patients will receive the combination of lanbatinib with pembrolizumab until progressive disease. And we hope that we can try to make things better with this combination for patients with vulvar cancer as well. So to sum up, what do we know about potential approaches to metastatic vulvar cancer? The first thing you should ask yourself when you have such a patient is, is there an open study the patient can take part in? Because there are several basket studies that could potentially be suitable for the patient. Then the standard approach is at this time point, a platinum based combination, first line therapy. And the question of maintenance therapy or second line therapy must be based on tumor tissue analysis. This could be NGS, but if NGS is not available at this point, it should be at least a PDL1 overexpression determined. So if it's overexpressed, checkpoint inhibition can be an individual approach. If not, EGFR targeting might be the better choice for these patients. And of course, it's always an individual approach and has to be reimbursed. And this is, of course, very different in the different countries. Thank you very much. Excellent, Lynn. Thanks a lot for this great presentation and congratulations for setting up this kind of study in such a difficult setting. Vulvar cancer is really not the area where it's easy to do clinical studies at all, and especially none with medical treatments. And so we're really excited to get this started and to hopefully recruit patients soon and of course, see interesting results there. So now the stage is open for discussion. And again, thanks to the great audience, we already received quite a few questions. I'm not sure if we will be able to address all of them in the setting of this discussion now, but I already discussed with all the different presenters that they will in parallel try to reply to you also through the website. And if the questions you ask cannot be addressed in our discussions, just email the presenters directly afterwards, and they will be happy to answer any question also there. So Dave, you received quite a few questions for your presentation, and maybe you can give a quick comment on the role of brachytherapy in vulvar cancer. That's a question that many asked. Okay, I'll try to be direct. I think it's very complicated because typically you do brachytherapy in the dorsal lithotomy position, and then you would treat in a different position with the legs down. And when you do that, the catheters you lay may be pushed together or spread apart. So I think it's very complicated. Having said that, if you perform the procedure and you can treat in the same position, it may work quite nicely. So I think it's very operator dependent, but from my own experience, and that's limited, I would say it's very challenging. And I'd appreciate what other people have to say on this topic. Okay, Anuja, you want to add anything there? No, I agree. I think there's a lot of experience from India, and actually Amish, who was asking about it, has a lot of experience doing it. So I think it is where you can do brachytherapy on certain vulvar cancers, but you really have to have the experience to do it. All right. Dave, since your mic is still open, another question for you. Can you comment on neoadjuvant chemoradiation for vulvar cancer? Maybe, I mean, it's something that probably you also use, at least we in Germany use it every once in a while. And also on the patients, you would use this approach. Yeah. So thanks. Thank you for that question. So it's hard for me to define specifically who should receive that neoadjuvant therapy. Basically, very large tumors. I think it has to be a discussion with the surgeon. If they feel that they cannot be removed without a very severe approach or exonerative approach, I would say in the United States, a neoadjuvant chemoradiotherapy approach is pretty standard. There's been several decades of GOG studies showing efficacy. In the GOG studies, they've gone up from 45 to 56 gray now to 64 gray. And as they've gone up, we've realized that we have been on the steep portion of the dose response curve. So in other words, pathologic control rates are markedly higher with higher doses. So I think it's an area where we need more data, but I think it can be an effective approach. I think patients who are getting a higher dose, they may not need surgery. And I think Dr. Noyes's presentation, the first one off, if we could fractionate our patients into HPV positive and P53 mutated or not, we may find out who are the responders and who aren't. So I think there's work to be done. And these are team decisions and we need good teams to manage these difficult problems. I mean, it's really striking to see the efficacy of radiotherapy in liver cancer. So the majority of patients have complete remissions after radiochemotherapy. And so, as you said, it's hard to select patients that do need additional treatments and it would be interesting to hear the international comments on that. But in our center, for example, if it was a large tumor after radiotherapy or radiochemotherapy, we first do multiple biopsies, mapping biopsies, and if we don't find any tumor anymore, we don't do large radical excisions just to put a large amount of healthy tissue to the pathology department and have wound healing problems afterwards. I don't know, Arthur, do you want to comment on that and the Groningen perspective on the neoadjuvant treatment approaches? Although there's not real good evidence on it, but I fully agree with your policy and that's also our policy. And I also do agree with the fact that if you do that type of resection, you really need to do perform biopsies before that. And then also you have to wait quite a while before taking the biopsies. You need at least six to eight to 10 weeks before you start doing that kind of biopsies. And especially taking random biopsies is really random. So fully agree with what you're saying. This is a little bit off topic, but in anal cancer, we as radiotherapists would recommend no biopsy be done unless there was a palpable finding. So I agree with Atte, perhaps blind biopsies might not be serving us well and they should really have close observation. I think it's a very interesting topic. Absolutely, absolutely. And it is something where we might be able to, you know, gather some international database to get some more information on that because, you know, having these patients without biopsy afterwards does not feel good at the moment for us gynecologists. But looking over to anal cancer we can see at any time, yeah. So there's quite a few practical questions. Nadja, one of them is for you regarding suture material. So what suture material, and I would add also what technique for stitches do you use to adapt your plastic reconstructions for liver cancer? So we, for the anchorage sutures that have the most of tension on it, we use the Vicryl or Vicryl. And for all the other stitches we use Monocryl. And we do the Donati, is that a German? Donati is Italian, I would say. Donati was Italian. Yeah, but does everybody know what Donati stitches are? So we use the Donati stitches so we don't have tension on the wound itself. Maybe our radiation oncology friends don't know Donati stitches, but all the other ones would probably know them. So Georgia, since Donati is from Italy, do you want to comment, do you have different techniques for wound closure or different suture materials? You showed us some wonderful even video images from surgery. Maybe just a suggestion, when we are closing a groin wound, we have a lot of dead space because we remove a lot of soft tissue. And so we undermine the skin. And we normally take care to fulfill all the dead space. So with subsequent continuous sutures, with Vicryl, absorbable in a few days, and then we leave there a suction drain, just in the small space in which we cannot enclose the margins. So along the femoral vein, the smallest space that is possible. And this is also useful to reduce the tension on the final part of the suture, because all the tissues came back in their first position. And so there is no tension in the suture. In this way, we prevent the formation of lymphocytes, and mainly in the apex of the triangle. And this is the caudal part where normally the lymph tends to go. And this is the first advantage. And the second one is that there is no tension in the suture, so we prevent the lesions on the groin. Thanks, Georgia. And a couple of questions highlight the importance of tumor biology, where we get more and more insight also in liver cancer. And Linda, you gave a wonderful presentation at the beginning of this master session. And Lynn, you also referred to some of the aspects regarding medical treatment, of course. Maybe, can you both agree on something that you would recommend right away to put into routine practice? Would it be HPV status and p53 for everybody, or p53 and p16? Like in your publication, Lynn, for every patient with liver cancer, we should measure? Do you want to go first, Lynn? Okay. Well, I think we should use that knowledge more and more in the nearby future. And we should indeed incorporate HPV testing and p53 immunohistochemical status for all cervical cancers that we treat. But I think it's a bit too early to indeed adjust our treatment plan for these patients. First, we need to ensure that the oncological treatment is safe. If we did either omit or be less radical in HPV positive patients, we first need to investigate whether we can do that safely. But I think it's good to have it in the background of the clinician, to know whether or not the patient is HPV positive or negative and carries a p53 mutation. So Lynn, you have now two sentences to add, because from our technical support team, we received the message that we need to close the session. Dave, don't consider me rude, but I saw you have your hands raised, but we should discuss that afterwards once we close the session. But Lynn, you can comment on that. I think it's mandatory to determine HPV and p53 expression status, because I think it's not mandatory for treatment, but it's mandatory for surveillance, because the treatment doesn't start with cancer treatment, but with treatment of precancerous disease. And if you know the patient has a positive p53 mutation, you would probably treat for underlying chronic inflammatory disease. And you should be aware of this and you should be aware of the HPV status and then maybe even offer the patient HPV vaccination. And I think the dilemma is that we know that HPV positive patients have a better prognosis, respond better to radiotherapy, but the real problem are the other patients, because we know they have a poor prognosis and we don't really have anything to offer except surgery, you know. So thanks, Lynn. Thanks everybody for this really great discussion, especially thanks to all those raising the questions in the chat and in the discussion. And as you can see, we could go on for at least another half hour to discuss all this, but we also need some hot topics for next year's IGCS meeting, which will hopefully again take place in person in New York City, which is quite an interesting place to hold a conference. So we all look forward to it very much. And I would also like to thank everybody from the organizing committee who really did a great job organizing this conference. We first planned it in person, then we planned it as a hybrid meeting. Now it's a fully virtual meeting. So there was a lot of work going on prior to this conference. And two people I would like to thank especially are Mandy and Mary, who led us through all the preparations here. And of course, thanks and congratulations to Anna and Matt, who chair this year's IGCS meeting and also did a great job to put together this conference. And now everybody, please stay tuned on this channel here. There is, I think, a two-minute break now till six o'clock European time. And then there is an oral abstract session that also features late-breaking abstracts. And I'm sure it's going to be very interesting. And I wish everybody an interesting additional day of IGCS conference. And thank everybody for staying tuned with us here.

vulvar reconstruction

vulvar cancer treatment

primary wound closure

primary secondary wound healing

anatomical reconstruction

small defects

larger defects

random skin flaps

Limberg flap

Pupallevy advancement flap

axial pattern flaps

labial flap

pudendal thigh flap

defect location

prior radiation therapy