Please go ahead. Good morning, or good afternoon, everyone. Welcome to this master session on vulva cancer at this virtual IGCS meeting. My name is Aad van der Zee. I'm a gynecological oncologist from the University Medical Center in Groningen. And I will be moderating this session together with Dr. Michael Höckel from the University of Leipzig in Germany. We are very happy that you are joining us. We think that we have made a beautiful program that covers the most relevant issues nowadays in vulva cancer. It goes from etiology, pathology to surgical treatment and finally adjuvant treatment. And what especially is exciting, I think, is that we selected for this session, not the old dinosaurs, but the next generation. And therefore, I'm quite proud that this is an all-female session on vulva cancer, which I think is quite justified. So without any further delay, let's hear it from our first speaker, Dr. Joanne de Hulie. She is from the Radboud University Medical Center in Nijmegen. And she is a gynecologic oncologist practicing for now, I think, more than 15 years. So please, Dr. de Hulie, go ahead and talk about etiology and pathology of vulva cancer. Thank you very much, Atte, for the introduction. Ladies and gentlemen, first I would like to thank the IDCS for the invitation to give this lecture on liver cancer. It will be a challenge to discuss all the topics, but I will try. I do not have any disclosures. After the introduction, I will pay attention to the different types of liver cancer and their associated premalignancies. Afterwards, I will present the current insights in head and neck cancer, because also in head and neck cancer, there's more than one oncogenetic pathway, and it's important to learn from other malignancies. Last few years, there's some research about a possible third type of liver cancer, and I will discuss some aspects with respect to prognosis and treatment in the molecularly different types. And finally, I would like to present some thoughts for future research. While the whole world is focusing on the coronaviruses, especially COVID-19, I will focus on the most important virus for the gynecologic oncologist, which is the human papillomavirus, HPV. I would like to give an overview of what we know about the role of HPV in the oncogenesis and treatment. While cervical cancer is nearly 100% HPV-positive, in liver cancer, the minority of liver cancers is caused by HPV. Although liver cancer is rare, we know that the incidence is increasing. This is due to the aging population, but the increase is mainly in younger women under 60 years, which has a relation with HPV. Currently, we have yearly 400 new liver cancer patients in the Netherlands, which is a country with 70 million inhabitants. Our research group made this slide about the two pathways of liver cancer more than 10 years ago. It's generally accepted that there is an HPV-negative pathway related to the autoimmune disorder, Lyme sclerosis, with or without differentiated VIN. This is HPV-negative, and the HPV-positive pathway is associated with the premalignancy usual VIN in this slide. But nowadays, we speak not about usual VIN anymore, but we use the term high-grade squamous cell intraepithelial lesion, the so-called high cell. In those days, we performed an in-depth study to characterize different tumor types dependent of associated premalignancy, HPV, P16, P53. And in fact, in blue, you see the classical HPV-related pathway related with high cell of the vulva, positive HPV, positive P16, and a negative P53. In green, you see the HPV-negative pathway related to DVIN, which is mainly P16-negative and P53-positive. The background of presenting this slide is to show that already more than 10 years ago, we recognized the two major oncogenetic pathway. But the question arises whether there's more, because not all cases fully follow these characteristics. But I will start to focus on the two main types. Here, you see some examples of vulvar cancers related to lyme and sclerosis. And here, you see two patients with an HPV-related vulvar cancer in a background of high cell. The third patient has high cell of the vulva and an anal cancer. It's important to realize that HPV can lead to premalignancies and malignancy of the whole lower genital tract. One of the aims of the International Society for the Study on the Vulvofaginal Disease, the ISSVD, is to optimally characterize and define the premalignancies. Here, you see the historical overview. And it's important, especially when you read literature and compare different papers, that you use the right classification. dVIN is a difficult diagnosis for both the clinician and the pathologist. So it took some time before differentiated VIN got a good position in the classification. Unfortunately, VIN 1, 2, 3 is still used in clinical practice. And I would like to invite all clinicians to discuss the current terminology with your pathologists to prevent using different classifications. In 2004, the ISSVD introduced usual VIN. And the term dVIN is sometimes a bit confusing because differentiated suggests a relatively favorable disease, while the risk of malignant progression in dVIN is clearly much higher compared to the HPV-related high cell. The fact is that the anal region and vulvar region are very close. And discussions developed about the terminology. Finally, it was concluded that using the same name is in anal, cervical, and vulvar regions. It's most easy for further discussions. But there are some unanswered issues about the clinical value of the term low cell. Because in fact, it's only an HPV infect. So I would suggest to be reluctant with treating low cell. The most important is the high cell, which is the premalignant lesion. Here you see the current classification, which makes discussions with other gynecologists, dermatologists, and pathologists easier. So I would suggest use high grade cell, so high cell, and the differentiated VIN. Here you see some clinical pictures and pathology pictures of high cell and differentiated VIN. And here it's quite easy to recognize and to differentiate, but it's not always that easy. So far, I think there are two pathways, HPV positive and negative. And each pathway has an own associated premalignancy. And I would encourage to use the ISSVD classification of 2015. Regarding oncogenesis and influence on treatment, it may be worthwhile to have a look at other malignancies where HPV plays a role. Therefore, I would like to pay attention to head and neck cancers. Head and neck cancer is a collective name of different entities. About 90% consists of squamous cell carcinoma, which is more or less comparable with filter cancer. Head and neck cancers develop mostly via one of the primary carcinogenic routes, namely on one hand, exposure to tobacco and alcohol abuse, which are known to be synergistic, and on the other hand, by HPV. While the cancers due to tobacco and alcohol decrease or stabilize in number, the HPV related tumors is increasing. Literature reported 25% to 60% of the head and neck cancers are HPV related, and it makes the head and neck region after cervix, the second most common HPV positive tumor site. 90% of the head and neck cancers are HPV 16. Here you see an overview of the two pathways. It's interesting to compare these characteristics with filter cancer. The number of HPV positive head and neck cancers is increasing, and in general, these patients are younger, so far comparable with filter cancer. A remarkable difference is the relation with socioeconomic status. HPV positive head and neck cancer patients have a higher status, while we know mainly from cervical and partly of filter cancer that HPV is more often correlated with smoking and lower socioeconomic status. In head and neck cancer, there are differences in location related to the oncogenesis. The prognosis in HPV related head and neck cancer appears to be better. Treatment of head and neck cancer is mainly surgery, but in the most cases, radiotherapy. The five-year survival is dependent of the HPV status. In 2012, three genetic subclasses were suggested by Lehmans et al., containing HPV positive tumors and a subdivision of HPV negative tumors with high or low number of genetic changes. With this further classification have not led yet to further differentiation in therapies. They already know that the survival is also influenced by the pack years of smoking. Despite existing evidence that human papillomavirus positive oropharyngeal cancers has a favorable prognosis compared to the HPV negative ones, randomized studies have not yet to report the effect of de-escalation radiation therapy. The aim of the study by Gabini et al. was to assess the effectiveness of those de-escalation. In more than 700 patients with HPV positive oropharyngeal cancers, they found a comparable survival, which is interesting and for the future. A recent Cochrane review summarized literature on standard post-operative hemoradiation versus the de-intensified treatment after local surgery. All phase three studies are ongoing now and results of the first phase three study is expected next year, which may be interesting also for treatment of fever cancer. In summary, in head and neck cancer, there are also different oncogenetic pathways, which are mainly, and the HPV positive patients are mainly patients with a higher socioeconomic status with a better prognosis. Smoking and PEG years are important for prognosis, and the smoking and PEG years are quite important. And maybe in the future, there's a role for de-intensified therapy in patients with HPV positive tumors. Here you see the two oncogenetic pathways in fever cancer we know. The last few years, there's increasing attention for a possible third pathway that's related to warthog p53, where discussions are ongoing on the exact mechanism of the oncogenesis and the possible associated premalignancy. The research group of Mariette van Poelgeest from Leiden has performed a very interesting study to characterize the different subtypes of fever cancer based on next generation sequencing. Moreover, they performed p53 immunohistochemistry, HPV, and all slides were reviewed. The inclusion of patients with VAD, fever acanthosis with altered differentiation, and ligand simplex chronicus is an additional interesting aspect because there is limited knowledge yet on these fever diseases that might be considered as premalignant conditions. Number A gives an overview of the premalignancies and figure B about the malignancies. And here, the red are the HPV positive cases. The HPV positive cases show nearly mutations. And the HPV negative samples, this group, are the p53 mutations. But there's also a subset which are p53 negative, but they have other somatic mutations. So they found somatic mutations with comparable patterns in premalignancies and the malignancies. And just like in head and neck cancer, a third type of fever cancer is defined based on molecular analysis. The question arises what influences should be on future treatment. So in the oncogenesis of fever cancer, there's more than the two pathways we know. As you can see in the HPV negative pathway, there is not one molecular subtype. Exact knowledge is lacking about the possible third type and the associated premalignancy. What would be the influence on treatment and prognosis? Prognosis and treatment is the next topic. Primary treatment is important, but the long-term follow-up of the fever cancer in the Groin HPV1 central lymph node study shows that a high number of 40% of the patients develop local recurrence. So we have a serious problem. And I will give an overview about two major pathways with this aspect. We questioned what the difference is in prognosis between HPV positive and negative fever cancers. We did a study at the Radboud UMC and we analyzed data of all patients with primary fever cancers between 1988 and January 2015. We investigated charge for patient treatment and tumor characteristic and follow-up. Histological specimen were reviewed and we performed HPV and P16. We found in more than 300 patients that the majority of patients had a non-HPV related pathway and 70% were HPV positive. The more invading tumors led to more positive lymph nodes. And patients smoked more often in the HPV related group and tumors were larger and more invading in a non-HPV related group. This figure shows the total disease specific survival curves of patients with HPV negative, HPV related, the green line, and the patients with the non-HPV related fever cancers, the pink line. Patients with HPV related fever cancer had a significant better disease specific survival. This clinical picture shows a patient with a recurrence after radical vulvectomy. It was earlier shown that extremely radical surgery does not prevent recurrences. Therefore, currently, wide local excision is the first choice of treatment in combination with a central lymph node procedure or inguinal femoral lymphadenectomy. The tumor-free margin distance is still under debate and the question is whether a tumor-free margin less than eight millimeters leads to a higher local recurrence rate that remains unanswered yet. Second, there is no difference in treatment and follow-up between patients with different precursor lesions. So the question is, which patient is at a higher risk for local recurrence? This brings us to an aim of the study we performed together with the colleagues of the University Medical Center Groningen. And we wanted to determine the incidence of local recurrence and then what's the role of tumor-free margin, what's the role of the precursor lesion, and can we identify a lower risk group? Here you see an overview and in fact, it was confirmed that there's a high local recurrence rate after 10 years. And it's remarkable that in both centers had exactly the same number of local recurrences, a little bit above 40%. Let's first focus on the pathologic tumor-free margin distance. In this table, we show that the margin distance had no effect on the local recurrence rate nor as continuous value, nor using the commonly used cut-off value of eight millimeter or five or three. When patients with adjuvant radiotherapy on the vulva were excluded the right column of the table, there was no evidence of effect for more local recurrences. In case of a smaller tumor-free margin, there was no elevated number of recurrences. So what's the prognostic value of a precursor lesion in the margin? We showed that patients with DEFEN in the margin, with or without LS in the margin, have a significant higher local recurrence rate compared to patients without a pre-malignancy or a high cell in the margin. We aim to determine the prognostic value of the presence of this precursor lesion. Let's have a closer look. And the risk with DEFEN or LS in the margin is about 40 to 50%. And patients with high cell in the margin have 17% risk on a local recurrence. It's much lower, but it's not low enough to say that the risk is extremely low. So we cannot identify a patient group with a very low risk. How about the influence on radiotherapy and the different subtypes? Lee studied 57 patients who underwent radiotherapy and found a relatively high rate of HPV-positive patients. In fact, the minority was HPV-dependent, but there was a big difference in response in the P16, which is comparable with the HPV-positive pathway, and the HPV-negative ones. And recently, the group of Jessica McElpine from Canada shows comparable results. They suggested and concluded, implications may include radiation dose de-escalation for HPV-related fever cancer and an increased surgical aggressiveness for the HPV-negative fever cancers. But why are there those differences in clinical outcome? Has it only to do with HPV? Recently, the group from Leiden studied the immune infiltrate in the different molecular subtypes of fever cancer. And they found high numbers of activated T-helper cells and an association with a better clinical outcome. And it was irrespective of HPV or P53 status. So the question arises whether there might be a place for immunotherapy. And remarkable, part of the HPV-negative tumors had a comparable pattern as the HPV-positive tumors. What should be the impact on treatment? So when we look at the prognosis and treatment, I think HPV-related fever cancer has a better prognosis with a lower local recurrence rate. And maybe there are limited literature. Maybe they have a better response on radiotherapy. There is still an overall high local recurrence rate of 40%. And there's no evidence that tumor-free margins should be more than 8 millimeters to prevent a local recurrence. D-fin and Ligand sclerosis is at high risk for a local recurrence. And I think all patients with fever cancer still need a long-term follow-up. Anyway, there are very many differences between the different patients and between the different situations. So I think in future research, we should focus on individualization. I think at least we should characterize the third pathway. Is there a place for less radical surgery in HPV-related pathway? And I think we should focus on the prevention of de novo local recurrences. The HPV-negative pathway, maybe we have to focus on more intensive local treatment, for example, with corticosteroids in the Ligand sclerosis patients. And maybe there's more place for immunotherapy in HPV-positive tumors. And I think also the next year, we should have a good look at results of further research in non-cardiological malignancies, because I think we can learn from that. I would like to thank my colleagues from the University Medical Center Groningen and the Radboud University Medical Center for collaboration in this research. I would like to thank you for your attention, and I'm more than happy to answer questions. Thank you. Thank you, Dr. de Huling, for this very nice and comprehensive overview of the etiology and pathology of vulva cancer. At this time, we do not have the opportunity to ask questions. And I'm now handing over the session to our next moderator, Dr. Michael Huckel. Michael, please go ahead. Hello. Hello, everybody. Hello, everybody. I don't see my face on the screen, but I hope you will see it. I'm also a gynecological oncologist working in Germany, Leipzig, Essen, and Munich. And I'd like to introduce the next topic of the session on vulvar cancer, which is, of course, treatment. And treatment of early vulvar cancer is traditionally by surgery. This kind of surgery is based on a anatomy which is functional. It is also based, and we have heard this in the previous lecture, on the idea of isotropic local tumor spread, which is, I tell it right now, wrong. And that's also the reason why the problem with Marching Woods is to be debated. And it's also, the conventional treatment is also depending on adjuvant radiation, as we have heard it right now, particularly in the nodal positive case. This conventional treatment, which has a high frequency of local recurrences, we have just heard this, is challenged by a new concept of treatment, which is not based on functional anatomy, but on ontogenetic anatomy, that is anatomy which is determined by the embryological development and leads to completely different structures in terms of what will be relevant for tumor spread. That treatment, which has been successfully applied in a lot of cancers in gynecology, oncology, does not need adjuvant radiation because all the cancer cells at risk are removed by the surgical technique. And this treatment is challenged, and this treatment challenges the standard treatment, and we will get further details on both kind of treatments from our speakers. At first, we will get to know the current standard of care, which is presented by Dr. Ong from Groningen, Netherlands. Please, Dr. Ong. Yes, Professor Hoekel, thank you for the introduction, and thank you to the IGCS for giving me the opportunity to give today's presentation. In this presentation, I will give an overview of the current standard of care of early-stage vulva cancer. I have no disclosures. There are two sites that need treatment in early-stage vulva cancer, the vulva and the groin. First, we will discuss the treatment of the primary tumor, and after that, how we should treat the groin. In this part, I will also discuss the results of our soon-to-be-published GroinV2 study. First, vulva treatment. The first-choice treatment of the primary tumor in early-stage vulva cancer is surgery. Of course, we know radiotherapy is also an option, but when talking about early-stage disease, this is not so common. The recommended treatment in these circumstances is a wide-local excision of the primary tumor. Some gynecologists prefer a radical vulvectomy, for example, because of widespread premalignant disease. The question is whether radical vulvectomy gives such a reduction in local recurrence rate that this outweighs the increase in morbidity. Data to support this are lacking, and therefore, a wide-local excision is performed in most cases. Joanna de Helle already gave an excellent overview of the discussion on a margin status, and therefore, I will keep this short for now. In a study that was a collaboration between Nijmegen and Groningen, we observed local recurrences frequently occurred in patients with vulva cancer, in up to 40% of all patients. And we also observed that they are associated with the presence of differentiated fin and leukemia sclerosis rather than any tumor-free margin distance. And therefore, we believe a more narrow tumor-free margin can be recommended than the eight millimeter that was aimed for in the last decades. And then the groin treatment. In 2008, we published the results of our first groin-sphere study. This study aimed to answer the question, is it safe to omit an incronal femoral lymphadenectomy in vulva cancer patients with a negative central node? And the central node procedure was performed in patients with primary squamous cell carcinoma of the vulva. They all should have had a unifocal disease, less than four centimeters, and no suspicious groin nodes. The groin recurrence rate after negative central node in this study was 2.3%. And it was a major decrease in treatment-related morbidity as is shown in this table. Therefore, since then, the central node procedure is more and more part of standard treatment in early stage vulva cancer. The indications for a lymphadenectomy are tumors larger than four centimeters, multifocal tumors, patients with recurrent disease who had previously a negative central node, and of course, the patients with a metastatic central node. Groin-Sphere 2 aimed to find a treatment option for the patient with a recurrent disease Phase 2 aimed to find a treatment option associated with less treatment-related morbidity for the central node-positive patients. The aim of the study was to investigate the efficacy of radiotherapy to the groins in vulva cancer patients with a metastatic central node. It was a prospective Phase 2 treatment trial. The primary outcome was the number of groin recurrences. The secondary outcome, the treatment-related morbidity. It was an international study with inclusion from December 2005 until October 2016. The inclusion criteria were the same as the first Groin-Sphere study, and there were stopping rules for the number of groin recurrences. When the central node was negative, patients were followed up, and when the central node was positive, they received radiotherapy to the groin with a total dose of 50 gray. And this is the flowchart of the study. 1708 patients were registered, and finally, 1540 patients were eligible for the study. 1218 had a negative central node, and 322 had a positive central node. Unfortunately, in June 2010, the stopping rule was activated after 54 months of inclusion. At that moment, 82 patients with a metastatic central node were on study, and nine groin recurrences had occurred. We stopped the study at that moment and performed an interim analysis, and we saw that patients at risk for groin recurrence had metastasis larger than two millimeter and or extra nodal tumor growth. At that moment, the protocol was amended, and we decided to proceed the study with only the patients with micrometastasis receiving radiotherapy, and the patients with micrometastasis underwent lymphadenectomy and post-operative radiotherapy when indicated. So that was in case of more than one positive lymph node or extra nodal tumor growth. And here you see there were 160 patients with micrometastasis and 162 with micrometastasis. And I will first show you the results of the patients with the central node micrometastasis. There were 160 patients with micrometastasis in the central node, and finally, 127 received radiotherapy to the groins, 50 patients had a lymphadenectomy after all, and 18 patients received no adjuvant treatment. In this graph, you see the isolated groin recurrence rate for patients with central node micrometastasis, and the blue line are the patients who received radiotherapy to the groins, and they had, after two years, a groin recurrence rate of 1.8%. And in the green line, you see the patients who received no adjuvant treatment, and you see the groin recurrence rate after two years was there, 15.4%. So I think this shows that patients with central node micrometastasis do need adjuvant treatment. And then the patients with the macrometastasis. There were a total of 162, and when you look here, you see 52 received radiotherapy, 104 underwent a lymphadenectomy, and six patients underwent no treatment at all. And in this graph, you see the groin recurrence rate of the radiotherapy versus the inguinal micrometastasis, the inguinal femoral lymphadenectomy in green. And you see the groin recurrence rate after radiotherapy is much higher, with 25% versus 8.2% at two years. And this shows the radiotherapy for this group of patients is not sufficient enough. And then the patients with a negative central node. In Groins V2, we still registered all patients with a central node negative, who were central node negative, and in total, 1,218 patients were registered. 36 isolated groin recurrences were observed in this group. When we looked into these groin recurrences, we saw six had a clear protocol violation because incomplete treatment of the groin, because the primary tumor was larger than four centimeters, and because not all central nodes had been removed. When you exclude these protocol violations, we have a groin recurrence rate of 2.5%, with a 95% confidence interval of 1.7 until 3.5. And that is approximately the same as in the first Groins V study. Also, these patients had an excellent disease-specific survival with 97.6% after two years. This shows the morbidity of all patients in Groins V2. In gray, you see the patients who underwent a lymphadenectomy. In orange, the patients who underwent central node with radiotherapy, and in blue, the patients who underwent a central node removal only. And you see that edema at six months post-treatment is the highest in the patients who underwent a lymphadenectomy, but that the percentage decreases in time, and also for recurrent infections, the risk was the highest in the patients who underwent a lymphadenectomy. And this shows the survival of all patients. You see the central node negative patients and the patients with macrometastasis have an excellent survival with 97.9 and 92.5% two-year disease-specific survival. And for the patients with a macrometastasis in the central node, it was 72.4%. So we conclude from this that radiotherapy to the groins in patients with central node metastasis smaller than two millimeter results in a very low groin recurrence rate, and that radiotherapy to the groins is associated with minimal treatment-related morbidity. We also showed that omitting lymphadenectomy in patients with vulva cancer smaller than four centimeter and a negative central node is safe, confirming the results of the first groins-V study, and that for patients with macrometastasis, radiotherapy with a total dose of 50 gray is not a safe alternative for a lymphadenectomy. We just started our groins-V3 study, and this study aims to answer the question, is radiochemotherapy a safe alternative for the lymphadenectomy in patients with macrometastasis in the central node, in order to also find a better treatment option for those patients? In order to increase the effectiveness of treatment, we want to increase the radiotherapy dose to 56 gray, and we will combine it with Cisplatin weekly. So the conclusions. For treatment of early-stage vulva cancer. For the vulva treatment, we recommend a wide local excision with the aim to aim for tumor-free margins, and you don't have to aim for more than eight millimeters. And you should realize that residual premalignant disease, especially the DFIN, combined with legion sclerosis, has a very high risk of local recurrence, and you can wonder if you should follow up with these patients in a different way. For groin treatment, in a unifocal tumor less than four centimeter, you can perform the central node procedure. When the central node is negative, follow-up is indicated. When the central node contains macrometastasis, they can be treated with radiotherapy or a lymphadenectomy, but you can discuss both options with your patient. For the patients with metastasis larger than two millimeter, a lymphadenectomy is indicated, or you can join the Crohn's V3 study. For tumors larger than four centimeter or multifocal disease, a lymphadenectomy is indicated. I want to thank you for your attention. Thank you, Dr. Ong, for your presentation, containing very interesting data, very interesting results, which are derived from carefully projected and carried out studies in your institutions. We are thankful for these numbers because they show clearly, that's a current idea, what vulvar cancer is and how vulvar cancer is spreading, both locally and regionally, is obviously not optimal. So I call Nadja Dornhofer to present a new concept of tumor spread and its translation into a new tumor staging, which comes closer to the real tumor and finally to a new therapy, which resets the tumor and its metastasis more accurate to its presence in the tissue. Please, Nadja. Yes, thank you very much for the introduction, Michael. Thank you very much to the faculty to give us, that you give us a chance to present our hypothesis on cancer-filled surgery for vulvar carcinoma as an alternative approach and to update our results. In the next few minutes, I want to talk a little bit about the principle of standard surgeries. Then I would like to briefly introduce the cancer field theory, give you a short overview about ontogenetic anatomy, ontogenetic staging, that then finally leads to the cancer-filled surgery for vulvar cancer, and give you a very brief insight into our results. First to the principles of standard surgery. So this is a illustration of an infective organ system. So here is an organ, here's a stroma of the organ, and here's the epithelium. Somewhere in this organ, for example, in the epithelium, now a tumor arises. So now the standard theory of local tumor growth expects this tumor to grow isotropic, diffuse in all directions, like a slow motion explosion. The surgical concept derived from this aims to resect this tumor with clear surgical margins that are metrically defined. Because one also thinks that tumor cells propagate in front of the tumor front so that these tissues surrounding have to be removed. So this is the consequence. And unfortunately, local recurrence rates are high. Therefore, in many cases, adjuvant chemoradiation or radiation is necessary. So, unfortunately, now, even though we combine two radical methods, more or less radical surgery, and radiation or radio chemoradiation, the price the patient has to pay is really high. Sometimes the impairment of quality of life is high, even though we combine these two radical methods. So we at the Leipzig School asked the question whether there is a possibility to improve the results, quality of life, and survival, just by changing the surgical approach. To do so, we have to aim for a new understanding or new perspective of local tumor spread. And that is the cancer field theory that I will give a short introduction to. So now we have our organ system again, So now we have our organ system again, this time in color. So the reddish area is our organ, stroma and epithelium. And this organ derives from a specific embryologic compartment. The grayish areas, they are neighboring organs or tissues that are neighbors, but they derive from an other embryologic compartment. So now we have the tumor that arises again, maybe from the epithelium. We hypothesize that this tumor does not grow like a slow motion explosion in all directions, diffuse or isotropic. We hypothesize that this tumor, first, for a very long time, infiltrates his homeland, his tissue of the same embryologic compartment, everything that you can see here in red. We further hypothesize that the borders of this compartment are tumor suppressive for a very long time. Of course, the further malignant progression continues, the more possibilities the tumor cells get. But for a very long time, they stay in their homeland in their embryologic compartment. So what does this mean for the surgical approach to this tumor? If we go a step back to look again on the standard surgery, we see that here two problems arise. We see tissue from the same embryologic compartment is left behind. And here there might be occult tumor cells and a recurrence can occur. The second problem with this approach is that we remove innocent neighboring tissue. The gray tissue could have been spared because it's neighbor tissue, but it's innocent because it is from a different embryologic compartment. So what would be the, in our eyes, of course, the correct surgical approach to this tumor? We believe we should resect the compartment. Not more. We should save neighboring compartments, but we should resect the compartment to finally spare radiation. Because we believe, and we can show some data to this, that when we resect the whole embryologic compartment, radiochemoradiation might not be necessary. So to translate this theory into a new surgical approach, we have to understand two more aspects. We have to understand the ontogenetic anatomy of the vulva, and we have to understand how tumor finally grows regarding the vulva. So if you look at this illustration of the vulva, everything you can see here is finally derived from the cloacal membrane. Here everything, which is shades of different shades of gray, is the cloacal membrane here. Then it further differentiates into the urogenital blade compartment, and finally the dark gray, the external genital compartment. And within this, further, the proper vulva field differentiates. And this is what belongs to the proper vulva. And I want to stress one point. You can see here that the outside of the labia majora does not belong to the proper vulva field. So the proper, because this is going to be important later. So the proper vulva field further has three subcompartments, oh, I'm sorry, the peripheral here in a light gray, the peripheral subcompartment, the intermediate subcompartment, and the central subcompartment. So how does tumor grow with perspective on these ontogenetic compartments? For OT1 tumors, this is our proposal for staging based on the ontogenetic cancer fields, OT1 tumors stay within one subcompartment. Here, for example, within the outer compartment, here in the intermediate compartment, and here in the central vulva subcompartment. Tumors in the stage OT2 grow within two subcompartments. Tumor stage OT3A can infiltrate tissues deriving from the external genital field, 3B also from the urogenital plate compartment. And of course, OT4 tumors can infiltrate all tissues derived from the cloacal membrane. So this ontogenetic staging, that this ontogenetic staging is not just a hocus pocus or alpacadabra, you can see at this slide. In our set of 110 patients, the ontogenetic staging is a very good prognostic factor. You can see here the survival, the C-specific survival for OT1, 2, and 3 tumors, and here nodal involvement. So for OT1 tumors, only 4% of these patients have nodal involvement, and the five-year survival rate is nearly 100%. For OT2, survival rate drops a little bit or to 80%, and consistent to this, the nodal involvement rises up to 44%. Tumor stage OT3A and 3B, survival rate drops further to nearly 60%, and 3A, 60% of patients have nodal involvement, and 3B, 100% of patients have nodal involvement. So we think that this is a very, very strong prognostic factor, much better than standard factors we have at the moment. So based on this ontogenetic tumor stage, we can now plan our surgical therapy that consists of local therapy, the vulva field resection, consists further of the anatomical reconstruction, and of the regional therapy of the lymph nodes. So first we have to decide what type of stage, ontogenetic tumor stage we have, OT1, OT2, OT3, AB. Small tumors, we can do a partial vulva field resection. For tumors that involve two subcompartments, we need to do a total vulva field resection. But we have several, we have six types of different vulva field resection, so it's not always necessary to remove the whole vulva field, to do a whole vulva field resection like this is shown here. We can also tailor it to the size of the tumor and to the position of the tumor. We can do an anterior vulva field resection, a posterior vulva field resection, or lateral vulva field resection. But I want to stress again that outside of the labia mayora can always be safe because here in these tumor stages, OT1 and OT2, of course, because here is the border of the compartment. So this is a big advantage, that now we have several easy to perform and safe flaps to do an anatomical reconstruction for our patients. We have the possibility to do a VY pubolabial advancement flap, a Limberg flap, labial flaps, or pudendal thigh flaps. What do we do with the regional surgical treatment? For small tumors, OT1 tumors, that infiltrate more than one millimeter, we do a sentinel lymph node biopsy. If this is positive, or if we have clinical positive nodes, we perform a therapeutic inguinal lymph node ectomy. We send them to frozen section. If there is metastasis, we do an ascending lymph node ectomy. We open the inguinal femoral ligament and we resect the distal pelvic lymph nodes through the inguinal ligament. And we send these again to the frozen section and go one lymph node station further up if these are positive. So what are the results? First of all, I wanted to show a short case. This was a young patient, 47 years old, with an OT1 tumor here in the intermediate subcompartment. That was the status after retraction. And this is the status after anatomical reconstruction with a pupillary labial advancement flap. Because it's an OT1 tumor, we performed a sentinel lymph node ectomy. And this is, I'm sorry, this is the picture six months after primer surgery. How are the survival rates for our 110 patients in the single center prospective cancer field surgery study? You can see only 10% of our patients have severe disturbance of body image compared to standard treatment, which is more than 50% of patients with severe body disturbance. And the recurrence-free survival rates for nodal negative patients are 100%. Of course, if we have a nodal involvement, the survival rates drop to 54%. But we have to bear in mind that none of these patients ever got radiation or chemoradiation. So for those of you who are interested in more details, you're welcome to read the publications we were able to publish on this. Or you're welcome to follow the session, Cancer Field Surgery, tomorrow morning at, I guess, 4 o'clock German time. Thank you very much. So thank you very much, Nadja, for this clear presentation of the systematics behind cancer field surgery. I think it became clear that the problem with the margin width is an anisotropic question because the margin, which is close to the cancer field border, could be very, very small. And the margin within the cancer field must be much greater depending on the aggressiveness of the tumor. So just the number is not the relevant thing, but where the margin is situated is relevant. And we need an anatomy which is specific for the tumor spread and not anatomy, which we have learned from the anatomy books, which is directed to function or to just arbitrariness. Now the program foresaw a debate. But I would suggest, and I ask Arthur if he would agree, that we also hear the last presentation and then have a debate all together. Because we had aspects of treatment even in the first lecture. And we had aspects of, for example, adjuvant treatment in other lectures too. So let's have all the information together and then debate standard versus a new concept of treatment. Is it OK, Arthur? Yeah, that's OK. Maybe I can ask a wonderful presentation by Nadja. Just have one question that struck me with respect to the prognostic significance of your ontogenetic staging in relations to the local recurrences. I wondered, what is the relation between the ontogenetic stage and size? And I also wondered whether you did a multivariate analysis to show whether this prognostic impact is really independent from size. Nadja? You have to turn on your microphone. Thank you very much. Can I show the slides again? No, you can just answer the question. Oh, OK. So of course, we see the tumor size also correlates to the ontogenetic tumor stage. But it is independent from tumor size. So it's not just that the tumor size influences the survival rate. It's independent. So the ontogenetic tumor stage is independent from tumor size. And of course, the smaller the tumor, the more likely it is a small also ontogenetic tumor stage. But we also have four or five, well, let's say four centimeter big tumors that are OT1 because they are only involving one subcompartment. And we have small tumors that is maybe only one or two centimeters that involve two subcompartments, so are OT2. And still, the prognostic factor is depending on the ontogenetic stage and not on the tumor size. So that is actually quite clear. OK, thank you. Well, Michael, I think it's an excellent idea now to proceed with the session with the presentation by Dr. Lynn Wilber. And then we will have the debate at the last part of the session. So then I think you should introduce Lynn Wilber now for us. OK. Lynn Wilber is from Hamburg, Professor Lynn Wilber. And she did a lot of research with respect to Wilber cancer, particularly in looking at great numbers retrospectively and also gaining interesting and very important clinical data, which is the basis for any progress. Please, Lynn Wilber. Thank you very much. So as Professor Höcker already said, I think a lot of the data I wanted to share with you has already been discussed by my previous speaker. So I will try to sum up things to broaden the range for the discussion we will have afterwards. So these are my disclosures. So if we talk about adjuvant therapy in Wilber cancer, we usually talk about adjuvant radiotherapy. And if we talk about adjuvant radiotherapy, we have to talk about the fields we want to irradiate. And those can be divided in local radiotherapy of the vulva and the therapy of the lymphatic. So I want to start out with the adjuvant radiotherapy of the vulva, which is a very difficult field to discuss, as you already heard from my previous speakers. And the data Professor De Hullo showed you, I will just shortly go into that again, because we really have gathered data regarding the risk, the high risk for local recurrence in our patients with vulva cancer. And that risk is persistent over years and years after primary diagnosis, so it stays with the patient. And we also know that patients that develop local recurrence have consequently a decreased disease-specific survival. And that was something new for us, because we always thought that local recurrence wasn't that important for further prognosis. And I think this study from the Netherlands is very nice, because it's somewhat an explanation for the different reported local recurrence rates in vulva cancer, because it shows that dependent on the length of follow-up, the reported recurrence rates, local recurrence rates are getting higher and higher, with a yearly recurrence rate of around 4%. This is also shown in the AGO CARE study, which was a German study Professor Höcke was talking about, where we collected data sets from over 1,600 patients with vulva cancer. And also in this study, very much in line with the data from the Netherlands, we could show this very high recurrence rate of 40% after 10 years. And if you look at the curves for the other disease recurrence localizations, you see that those occur, those recurrences occur early in the course of disease, and then just sort of fade away, and opposite to the local recurrences that can occur very late. This also leads, of course, to the idea that those are the novel tumors arising from underlying skin diseases. So if we want to identify patients at high risk for local recurrence, that's a difficult thing based on the data that has been published. And only recently, we have shed some more light on the real factors that are important for local recurrence. But what is still very important is, here, we also see data from the AGO CARE study, that patients with nodal metastasis are at the highest risk for local recurrence as well. They have double the risk for local recurrence. And we actually still don't know the answer why this is the case. And if you compare the risk, the hazard ratios, for local recurrence, and for the different clinical pathological factors that were investigated in this study, you see that the lymph node status is the most important factor, actually. So what do we make of this for the indication criteria regarding adjuvant regular therapy of the vulva? So as I told you, that's a very difficult question, actually. We only have one solid criterion, and that would be, if we cannot resect the tumour totally and cannot do a re-excision, we have very good data that, in that case, we really need to irradiate the vulva to prevent local recurrence. But all the other factors are much more difficult. And there has already been a lot of discussion or a lot of data presented regarding the resection margins. That's why I want to go over that a little bit more briefly. You know, all the data we have regarding the resection margin has very much the same problems, which are that we look at very heterogeneous cohorts, mostly because we have a mixture of node-positive and node-negative patients, a mixture of patients having received radiotherapy or not. So we see a high variability regarding reported local recurrence rates, and often there are no multivariate analysis performed. And I just want to show you another analysis from the ATO CARE study, which points into the same direction than the other recent studies we have heard about, and also that the margin is of much less importance than we always thought. In this study, we aimed for a very homogeneous cohort, so we just looked at the patients that were solely surgically treated and were node-negative. So we only had node-negative patients with R0 resection, no margin, and no further adjuvant treatment, and those were follow-up for about three years. And in this very homogeneous cohort, we could demonstrate again that the resection margin was of no importance for local recurrence, which was around 11 percent within these three years after recurrence, but this is probably because of the relatively short follow-up. These are the curves, but as the speakers before already told you, we could not identify an optimal margin, and that's probably because there is no optimal margin, as Professor Huckel also wanted to imply. So what could be the explanations? So there are multiple explanations, and the one thing is that we really need to look for the surgical successes based on the diagnosis of the underlying skin condition. So if we miss to treat the lichen sclerosis on which the cancer is based, the patient is at high risk for local recurrence. Also if we miss HPV-related diseases, that would make a big point. So if we don't have a good diagnosis, it's probably safer to do ultra-radical surgery. It's very provocative, I know, but it's just to illustrate that it's very important to have a safe diagnosis at the vulva and look for pre-malignant disease and underlying skin disease. And this is very nicely illustrated by the study from the Netherlands that Professor de Hulot showed you already, that the risk for local recurrence is very dependent on the disease you find in the margin. And this somehow can also be put into context with the cancer field theory, because the lichen sclerosis, you know, it respects, also respects the inner vulva and doesn't infiltrate the vagina, doesn't infiltrate the labia majora, so somehow, you know, even if we were to debate the oncogenic fields, it might come to the same point in the end. If you look at other studies that want to evaluate potential factors for, risk factors for local recurrence, and then consequently have an implication for the indication of active end radiotherapy, you know, it's very unconclusive. What you see is that the nodal status is a consistent risk factor for local recurrence, but we don't know if the irradiation of the vulva in no positive patients really lowers the risk for local recurrence in these patients. Nobody has investigated this so far. And we all see in the younger studies or we see in the younger studies that the HPV status is of great importance for local recurrence. So if I come back to the slides, what are, to the first slide, what is, what are potential criteria for the application of adjuvant radiotherapy? You know, it just stays the same. R1 resection is the only solid criterion. And you could, you have to debate with your patients with regard to the other factors, but it's basically no good data there to really have a hard indication for adjuvant radiotherapy of the vulva. So what about the lymphatics? That will be the next point I want to discuss. So the first question we have to ask ourselves is of course, for whom is adjuvant radiotherapy of the lymphatics important? And if you look at these curves, you know, you all know that nodal metastasis are the most important prognostic factor for all patients that we can improve prognosis for our patients by applying adjuvant radiotherapy in these patients. The problem still is that a lot of patients don't receive adjuvant radiotherapy, at least in Germany, because of comorbidity and other factors such as surgical morbidity, but that's, you know, they really should receive adjuvant treatment. So there has been a long ongoing debate on the indication criteria for adjuvant radiotherapy to the groin. And I think we all agree that from two and more positive lymph nodes in the groin, there should be adjuvant radiotherapy after full dissection of the groin. And then you see that there is a trend for positive effect of adjuvant radiotherapy in patients with only one positive groin node, but this has not been consistent in different studies. And that's probably, this is a retrospective series of the National Cancer Base showing a potential benefit, but probably this inconsistent effect of radiotherapy in patients with only one positive lymph node is based on the fact that the morphology of the metastasis has a great impact on the effect of radiotherapy. So how big is the metastasis? How's the spread of the metastasis? There have been some interesting publications on that already in the early 90s. But interestingly enough, all the guidelines come to the same conclusion. We see that adjuvant radiotherapy in not positive vulvar cancers recommended from more than one metastatic lymph node, or in case of one metastatic node with extra capsular lymph node involvement. And then in some countries, it's even advised if you have a metastasis greater than five or 10 millimeters. And there is a new indication criterion for adjuvant radiotherapy. And I don't want to go into detail again because Michael Wong already showed you the data. I just want to emphasize that I really want to congratulate the Broin 3.2 Study Group for performing this trial because I think it leads to major improvement for our patients. As you have seen, the morbidity of treatment can be reduced by not performing full groin dissections in patients with isolated micro metastasis in the sentinel lymph node. And that's new and should be implemented in clinical routine as soon as possible from what I think. So the next question, if we talk about adjuvant radiotherapy, of course has to focus on the question, what should we irradiate? And I think that's one of the favorite German questions actually, because currently it's mostly the case that if you indicate adjuvant groin radiotherapy for patients with positive lymph nodes in the groin, then the pelvis will automatically be irradiated as well. And the question is, why should we do this? And does it really make sense? So why do we actually do this? This is based on one of the very few randomized studies of vulvar cancer, the GOG37 study, which was already published in the 1980s, and which tried to answer the question of the optimal treatment of the pelvis in vulvar cancer. And patients in this study either received a complete vulvectomy, groin dissection, groin dissection, and a pelvic lymph node dissection, and no further treatment, or they received a vulvectomy, groin dissection, and then adjuvant radiotherapy of the groins and the pelvis. And this study was stopped due to a clear advantage for the radiotherapy arm. But from what I told you now, you already, you all know the answer why the radiotherapy arm was superior to the surgery arm, because adjuvant radiotherapy of the groin is necessary. And you see here in the surgery group, it's very high recurrence rate if you didn't perform, patients didn't receive adjuvant radiotherapy of the groin of 23.6% compared to only 5% in the patients group with adjuvant radiotherapy. But what you didn't see was a difference in pelvic recurrence rate actually, or even less recurrences if you did a pelvic lymphadenectomy. So what does that mean? It only means what we already know that it's very important to radiate the groin in patients with positive groin nodes. But it doesn't mean that we know that patients will benefit from adjuvant radiotherapy of the pelvis as well. We just perform adjuvant radiotherapy of the pelvis because we don't know better. We don't know which patients are at risk for pelvic metastasis, and will consequently benefit from adjuvant radiotherapy of the pelvis. And that's, I think, a point for future research. So to conclude, I just want to emphasize that the NCCM guidelines and the ESCO guidelines point out that based on the evidence in other squamous cell cancer, such as cervical cancer, head and neck cancer, and so on, we should consider using chemotherapy whenever we indicate adjuvant radiotherapy in vulvar cancer to higher the efficacy. And there are some very small series which deal with this subject, the prospective series, which show a potential benefit of the addition of chemotherapy to radiotherapy in the adjuvant treatment of vulvar cancer. But you know, these are only 22 patients. There has been a very interesting analysis from the National Cancer Database, which is, of course, with the restrictions of the retrospective analysis from the cancer database. But the colleagues here could show that chemotherapy in the end lowered the risk for mortality by nearly 40%. So adding chemotherapy to radiotherapy lowered the risk and in non-positive disease. But of course, one could argue that there would be a big selection bias in this retrospective database. So what are the take-home messages at this point? So there is a clear benefit for adjuvant radiotherapy from two and more positive groin nodes. And what's very important, I think, is that we still have to do better. So despite application of adjuvant radiotherapy, prognosis of these patients is still poor. So we can try to improve efficacy by adding chemotherapy, but I think it's still not enough in these patients. And there is a new indication for radiotherapy of the groin only, which is isolated mycomatosis according to the groin's V2 study. Thank you very much. Okay, we thank you for your clear presentation and a lot of very interesting, well-designed study data. And we have, I think now, the basis for a debate which we could spend for approximately 13 minutes. And I would like to open the debate and calling for a better surgery. Why we refer to radiotherapy? Why we refer to chemo radiotherapy when we know that the surgery which is underlying and is our principal field of treatment is not optimal? This is also true- Maybe just to interrupt you, because I would like to ask you and also Nadja the following question, because everybody, of course, is very much interested in your approach. The question that I have to you both is how are you going to bring this further? What is your idea on this? Because so far, of course, it's very impressive, but it is a single center experience. So what is your idea of Nadja idea? One of you can answer the question, I guess. How are you going to bring this further? Nadja. Nadja, you have to turn on your microphone. You are so patient with me, Arte, and repeat your hint. So if we want to take this further, I think we should aim to do multi-center studies, which in my opinion should also be not such a big problem and which we started already. So we have two more centers that also perform the vulva-fiatri section. Michael, did you want to say something? Yes, multi-center studies, just to demonstrate that our results are reproducible and can be performed by others are the most important next step. We have done this already for cervical cancer because cancer field surgery is not only applicable for vulva, is applicable in all oncology surgery. And we have much more patients and much more longer follow-up and data for cervical cancer. We also had for cervical cancer dispensed radiation and we could in long-term demonstrate the superior results. And now, and this will be demonstrated for the first time at this conference, IGCS conference, the first data of the multi-center study in cervical cancer confirmed our results. They got the same good local regional tumor control without any radiation, even better than our Leipzig data. Also the number of patients, 19, and the follow-up is not enough, but the trend is absolutely the same. And if you just look behind the logic of that concept and the problems which you have in the standard concept with the isotropic tumor distribution, then you, I think, must just because of logical thinking come to the idea that the conventional treatment with more and more radiotherapy and other adjuvants is not the solution for an approach which is not really treating the tumor. You treat a concept of the tumor which has to be falsified. So we really call for everyone doing oncologic surgery to rethink surgery in terms of treating the real tumor, not of the macroscopic thing with a margin, circumferential margin, but of the tumor which has, which needs some instruments to grow into the tissue, which is a property of the tumor cell. And the tumor cell is not a different cell than a normal cell. It has- Michael, sorry to interrupt you again, but I would like to ask, for example, Lynn, whether, because of course you need to do, to bring this further to other centers and then Lynn, for example, would you be interested to participate in such a study where you randomize, for example, patients between a radical local excision and field surgery? I have two resentments regarding this and that's also what I wanted to ask you, Michael. So the first thing is, what do the lymph nodes have to do with the vulva field resection? Because in the study you proposed, you also do not irradiate at event the lymphatics. So there's a mix up between these two, which I don't know if that will complicate the results maybe and the other thing is that, why to be provocative, why should I resect non-cancerous tissue with a lichen sclerosis in the same field when I could just treat the lichen? So that's just to bring more pepper into the discussion maybe. Okay, but let's not, Michael should not answer the question but Natia should answer the question, I think. Yes, so I would answer the second question first. So we are not usually, we are not resecting the lichen. So as I showed in my slide with the different types of vulva field resection, we don't always perform a whole or total vulva field resection. We tailor also, as others also do, our surgery to the size of the tumor and to the position of the tumor. And we do not resect only because of the lichen total vulva field. So we only do the total vulva field resection if we have a tumor stage, at least OT2, because we then know OT2 have a higher risk and that normally are larger tumors. Not always, as I explained before, we also have small tumors that are OT2. Then we also perform a total vulva field resection, but in general, if we have small tumor OT1, we do not resect the total vulva just because of lichen sclerosis. We rather treat the lichen sclerosis afterwards. But of course the patient have to know if there's a lichen sclerosis, they have a higher risk for a second primary. So not a local recurrence in our opinion, if it's developing at another area and maybe another sub-compartment, it's not a recurrence, it's sometimes also a second primary. So Nadja, are you, because your results in the T0 or T1s, OT1, is so good with respect to local recurrence. You could foresee, of course, a randomized trial where you need very little patients because it is so good. Is that one of the things that you are thinking of? Yes, yes, definitely. Okay, so I would then like to ask our Dutch colleagues, Dr. de Hulo and Dr. Ong, for example, would you be willing to participate in such a study, Dr. de Hulo? Thank you, Arthur. Yeah, I think it's an interesting discussion. I'm very impressed by the, in fact, quite extensive surgery. So I think it will not be so easy, I think, to introduce this in the Netherlands, but yeah, I think we should discuss it, but I'm a bit reluctant because of the extensive surgery. And what about Dr. Ong? Dr. Ong, are you still with us? Yes. You should think with that unmuting during the corona, you should be familiar with that, but it's still sometimes a problem. I would think so, yes. I also read in your paper that you have almost, I thought, 90% flap reconstructions, which indeed suggests that you do, well, extensive surgical approaches. And that's also why I would be, well, I'm not certain if I should, would want to participate in such a study because the resections seem to be much larger. And therefore I also wondered if you have quality of life data of those patients, and maybe you can say something about that. Yes. Okay, thank you, Dr. Ong. Two questions, in fact. Why are the rate of flap reconstruction so high in quite early stage tumors? And the second question is quality of life. Yes, so our resections, I guess, are not bigger than normal resection. In fact, I guess they are smaller in several cases. And we nearly reconstruct any patient, particularly the young patients. So we only do not reconstruct patients that are really old and really say they don't care about introitus or other functional problems. But for younger patients, and I mean with young also 70-year-old patients that are still active in their whole life, we regularly perform anatomic reconstruction for aesthetic and functional reasons, no matter how small the defect was. Of course, very small defects we do not reconstruct, but also a partial or anterior vulva field resection can be a big impairment if we do a primary wound closure. So we are really fans of anatomic reconstruction. And the conclusion that we then also do huge resections is simply not the right conclusion. Okay, thank you, Nadja. And unfortunately, we have now to close this session because we are running out of time. But before closing, I think we first would like to thank all the speakers in this sessions for their excellent contribution. I also would like to thank my co-chair, Professor Michael Huckel, for steering up this excellent debate. I really would like to see a multi-center study where this technique is going to be really evaluated in multiple centers. And I think that we could see for a way of doing this, also, for example, in the Netherlands. So I also would like to thank all the people that joined us for this session. And I would like to recommend to them to explore the rest of the meeting portal when the program is done for the day. There's a lot of more to see today. Stay tuned here to channel one because next up is the presidential plenary, the advocacy panel, and the IGCS business meeting for the next hour. So I would like to say goodbye to all of you and wish you all a very nice day, not in Rome, but just where you are in your homeland. Goodbye. Thank you.

vulva cancer

surgical treatment

adjuvant treatment

etiology

pathology

radiotherapy efficacy

wide local excision

individualized treatment

tumor spread

cancer field theory

cancer-filled surgery

standard of care

lymph node treatment