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Hello, everyone and welcome to our actual First Meal Oncology event uh within our Meal Education series. We've decided that um because meal education has grown so much that actually we would love to start introducing specialities within me education. So that those of you that have a specific interest around a speciality can actually create threads and be notified about more and more of the teaching that's going on. Um So you can like metal Oncology by clicking the follow button above you probably and you can also follow metal education as well. Also very, very quickly. If you are an Android user, we've got an app. I know we've got an app. So please, if you're an Android user, please go to your play store and download uh the app. You'll be one of the first to do it. It's only just come out on Android this week. Apple, it will come to you. We're just waiting for it to go through its approval process and then you'll find it in your store too. Um So as always pop the questions in the chat and Eina will answer them at the end. Um your feedback form will come to your inbox in about an hour and then um your certificate will be on your med account. Ok. So without any further ado, I'm going to introduce you to Georgina, who's gonna be telling you all about Sarcoma in insights? Thank you. Thank you so much and welcome everyone. Thank you so much for joining today. Um It's very exciting to be part of this series oncology, education and focusing on my specialty um or Subspecialty, which is sarcoma. Um So I'm a medical oncologist and I work in London on the Sarcoma Unit at UCL H. Um And I'm also an clinical associate professor uh for UCL Medical School. So, starting with the premise of sarcoma and what are sarcomas? So, sarcomas are very rare cancers and they are a very heterogeneous group of cancers that we'll talk about a lot um later in, in detail later, but they're derived from mesenchymal cells and that can be from bone muscle cartilage or connecting tissue. Their rarity comes from 1% of all counts globally. So that's about 20,000 patients a year and that's including gastrointestinal stromal tumors. These tumors are um more common in pediatric um patients and account for approximately 20% of pediatric cancers. So, sarcoma is a very broad term and when we sort of move on and dig into sort of what sarcomas mean, we can categorize into broad categories and then thinking more narrowly. So it's helpful, I think to structure it in terms of bone sarcomas and soft tissue sarcomas. So, starting with bone sarcomas, they are much rarer than soft tissue sarcomas and they account for approximately 15% of all sarcomas. So, osteosarcomas, ewing sarcomas and chondrosarcomas are the more common bones sarcomas. And there are a number of others such as giant cell tumors, et cetera. Soft tissue sarcomas are um much more common and they account for 80% of sarcomas. But even with in soft tissue sarcomas, there are a number of different other subtypes that are um sort of categorized slightly differently, such as rhabdomyosarcomas, other different types of sarcomas such as kosis or DF SPS. And then in the true soft tissue sarcoma group are things like leiomyosarcomas, liposarcomas, et cetera. Distinct to that. Initially, it can be grouped as one of the soft tissue sarcomas but is a bit more of a separate entity are gastrointestinal stromal tumors which account for about 5% of all sarcomas. So as I have said, sarcomas are rare, but what does that really mean? And then I think it's helpful just to put into context the numbers compared to some other different tumor types and some other non malignant diseases. And so you may remember on the first slide, approximately 20,000 patients a year. And so those numbers are akin to things like a ML and esophageal cancers. So the difference though, of course, with sarcomas is that sarcoma is not one entity, it's a very heterogeneous group as we've just talked about with the broad groupings of soft tissue bone and chest cancers. And what that really means is looking at this um classification. So this is the latest who classification of tumors of soft tissue and bone. And so, not only are sarcomas rare, they are very complicated. And so this classification from 2020 identified that there are over 100 and 50 different subtypes of sarcomas. They can arise at any site, they can be any size and any grade. And therefore, the rarity is deeply complex. So this is a nice sort of schemer to help to try to think more about the cell of origin of these types of cancers. And then um the sort of naming that we're used to from a clinical perspective in the clinic. So as I said, these are cancers that arise from mesenchymal stem cells and then undergo oncological hits at various stages during development and then become more differentiated cells from the original stem cells. And from each of these cell types that you'll see across um across the middle of this slide, adipocytes, et cetera. It those are the cells of origin of these different types of sarcoma. So, adipocytes for what is the cell of origin for a liposarcoma, chondrosarcomas for chondrosarcomas, chondrocytes, sorry for chondrosarcomas skeletal muscle cells are the basis of rhabdomyosarcomas stromal cells are the basis of synovial sarcomas, osteocytes for osteosarcomas neural cells for ewing sarcoma and fibroblasts for fibrosarcoma. And that's obviously in keeping with the differentiation from starting as the mesenchymal stem cell into a differentiated um cell in the body. So to put that into the context of a person where can these tumors arise from? And the real answer is almost anywhere. But I think this is a really nice helpful infographic, I think to help to put those names front of the cell types into context in your patient. So here in red is the soft tissue sarcomas and in blue, the bone sarcomas. So you'll see some names that we saw on that previous side here um highlighted but helpful for potential anatomical positions. Um but going through them. So, fibrosarcomas um of fibrous connective tissue and can classically be ex classically in the extremities but can be anywhere. Synovial sarcoma also connective tissue. So, classically in um extremities, desmoplastic small round cell tumors typically arise in the soft tissue of the abdomen. Uh malignant peripheral nerves, these tumors arising from nerves that can be anywhere in the body but can be um more commonly in extremities, leiomyosarcomas of smooth muscle that can arise anywhere, extremities or anywhere else in the trunk or abdomen. Pelvis, rhabdomyosarcomas from skeletal muscle equally can be um typically extremities but can arise anywhere in the pelvis or abdomen or chest liposarcomas from fat can arise anywhere gastrointestinal stroma tumors as the more distinct entity that we've mentioned already. Um But from the gastrointestinal tract and we'll just get down to the bottom to do the last soft tissues, angiosarcoma from blood vessels. So then the bone sarcomas in blue, you see osteosarcoma, ewing sarcoma, which uh um typically is a bone sarcoma can also arise in soft tissue and chondrosarcomas. So, thinking a little bit about when you, when you encounter a patient that you think might have a sarcoma or how does that, what does that look like? And the difficulty in er sarcoma medicine is the fact that that can look like a lot of things. Um And as those, those previous um slides demonstrated that these tumors can arise at any site in the body. And so therefore, the signs and symptoms can be very wide, wide reaching and different. So there's a lot of difference and it depends on the size and the location of the tumor. But here, I've just highlighted some of the anatomical sites that are, that are counted and the things that you, you might raise your suspicion of um certainly a malignancy and then moving forward that from obviously a sarcoma. So, thinking about extremity, sarcomas, um lumps or bumps and swellings anywhere on the body. And those lumps and bumps can be growing very fast and they can be painful, but sometimes they can be slow growing and they can be painless and that's dependent on the histological subtype. So, thinking about um a Sino sarcoma, for example, um may be fast growing and painful. But uh an alveolar soft part sarcoma may be slow growing and painless tumors can arise, of course, in the bones. As we've talked about, some can be in extremity bones or spinal tumors. And they have obviously distinct things like pain in the back, difficulty walking, potentially incontinence of bladder and bowel if there's a big tumor that's affecting the spinal cord tumors of the head and neck. Um, most uncommon can be osteosarcomas or rhabdomyosarcomas in that position and can cause other different sides of symptoms, like bulging of the eyes, double vision swelling in your sinuses, that could cause pain, difficulty swallowing or hearing, changing your voice bleeding from the nose, epistaxis, tumors in the thoracic cavity could cause symptoms like shortness of breath, chest pain, cough, he hemoptysis, um sorry, that's hemoptysis. Um arrhythmias and and hypertension and then the abdomen retroperitoneum and pelvis. And that can have a huge constellation of different signs and symptoms. Um thinking about effects on bowel, constipation, diarrhea, pr, bleeding, melena, abdominal pain, swelling, um and then more general um sort of symptoms of sensitivity with cancer, like feeling tired, weight loss, et cetera, thinking about tumors of the gyne tract, then of course, they can have things like um menorrhagia, excessive bleeding. So, the main take home message is that this is a complicated groups of cancer that can arise anywhere and have lots of different signs and symptoms. Things that you may encounter commonly are lumps and bumps of painful joints and painful limbs. And if you have a suspicion of those things, then think about sarcoma. So to make the diagnosis, what do we do next? Um Of course, you'll examine your patient and then we need some imaging and the things to do in the first instance, uh is a ultrasound X ray. And then depending of course, on the availability of, of um where you're working um and living other imaging is also helpful. So, of the primary site typically, MRI. Um and then for staging, we typically do CT and that would be a ct of the chest abdomen and pelvis, pet scan. Um and also bone scans, bone marrow biopsies, we do much less often. Now, um they have been used historically, particularly for bone tumors, things like ewing sarcoma or in pediatric populations and are done sometimes. But now, imaging with things like pet and MRI um are sufficient and useful. So to confirm your diagnosis, of course, you need to do a biopsy, take a sample of the tumor and to confirm your histological diagnosis and that can be done via a core biopsy or sometimes via an excision biopsy. So if we're thinking about somebody who's presented with a lump on their leg that is superficial in the subcutaneous tissues, they could have an ultrasound guided um biopsy, but they could sometimes have an excision biopsy and that helps us to grade and stage the tumor and confirm the surgical subtype. So it's really important for any cancer diagnosis, but particularly with sarcomas and how we frame things in the UK is that all new cancer diagnoses are discussed in a multidisciplinary team meeting. And that's also Akins to in other places around the world called tumor board. And um that is so that the a group of medical professionals looking after that, the patient can obviously decide the best course of action for that particular for that particular patient and that particular cancer type. So because sarcomas are rare in the UK, we have specialist sarcoma centers. And on the right, there is just a picture of where the bone cancer centers are. So you can see that across the country, there's a few centers across the UK, there are other centers that also look after patients with soft tissue sarcomas. That was the reason for specialist care being important because these are rare tumors. So who sits on the tumor board, it's radiologists, pathologists, surgeons, medical oncologists, like me, clinical oncologists that do radiation treatment, um pediatric oncologists and clinical nurse specialists. And that's also to thinking about holistically how we're looking after our patients. So in that meeting all of the imaging that has been done, if there's been a biopsy done, all of that is discussed to think about what's best and what's the next course of action and how we need to manage our patients. So thinking about how we treat sarcoma patients, I think it's helpful to think about it in these three sort of um broad terms and conventionally, um for a framework for you to think about how we should approach a sarcoma patient and their treatment. So, surgery is a huge mainstay of treatment. Um, whether that be a wide local excision depending on, of course, the down to site if it's laparoscopic surgery, if they have a tumor in the abdomen and pelvis, lots of patients end up having reconstructive surgery if they're having a limb salvage operation, for example, for an osteosarcoma. Um but of course, sometimes depending on the anatomical site, amputation is necessary. Um and thinking about sort of sequela of that for your patients um radiation treatment. So that's the other word, external beam, radiotherapy, sometimes brachytherapy, um proton beam radiation and intraoperative radiation. We also give lots of different chemotherapy drugs which I'm gonna talk about in, in uh a lot more detail uh later on. But that's a helpful framework. I think for you to think about how we approach this and we know that certainly for cure for these types of cancers. If people have got a localized disease, then the approach is to have surgical, have surgical intervention to um remove the cancer. And then thinking about whether you need any extra, whether that be neoadjuvant before an operation or after the operation, whether you need additional treatment with radiotherapy and or chemotherapy following initial treatment, people have follow up. So this is if we're thinking about a patient that has had um had their initial treatment, had surgery, radiotherapy and chemotherapy and their disease is no longer active and has been removed. Then we follow up patients for a long time, up to 10 years. Um and that can the exact sort of protocol for that depends on the histological subtype. And those follow up appointments are thinking about talking about their symptoms, physical examination and usually some sort of imaging such as a, an X ray plus a chest X ray or chest CT, depending on the tumor type, um to follow up and, and looking for signs of recurrence. If there is anything on your initial imaging, of course, that is concerning for a local recurrence or a metastatic recurrence of their tumor, then further scans are often warranted whether that be with a full staging scan, CT MRI of perhaps of the primary site or pet scan. Um if and when available. So we've talked about a lot of these um things already. But I think helpful just to think about why sarcoma is um has challenges in its management, the clinical and biological heterogeneity, which we've talked about um that can mean that patients present in all which ways in lots of different ways to their GP to hospital after a long time. Um And we commonly get a lot of patients that have um have had a misdiagnosis initially or a very delayed diagnosis. Um when you think about that, if you're thinking about young people, for example, where osteosarcomas and ewing sarcomas are a common cancer in teenagers and young Children. Um but aches and pains and growing pains in young Children are often misdiagnosed. So that can be troublesome. As I showed you in the UK, the geographical area that we cover is large and I'm sure that is the same across the globe. There is the geographic areas that you cover and that can create problems. Can't it for people trying to get to hospital where the referrals come for from, you know, whether the patients are able to get to the hospital, the financial implications of treatment and travel and things that means that the patient experience can be not ideal for lots of the for all of these reasons. And then from a medical oncology point of view, you think about treatments and so chemotherapy remains a a backbone of of treatment, but lots of these cancers don't respond very well to chemotherapy, but there are limited other therapies. There's a lot of research going on about how we can try to optimize um systemic treatments. And then thinking about clinical trials, which of course is, you know, search for new treatments, which is also always what we want. Um but that can be difficult and particularly because of the heterogeneity of this, of this patient population. Um that getting big cohorts of particular sarcoma subtypes to investigate can be more challenging. So we're gonna talk a bit more about um the different sarcoma subtypes now and management. So, focusing on soft tissue sarcoma first, which as you know now is the more common subtype. Um So this is a simplified version of that very complicated diagram. You may remember from the who classification but thinking about the more common sarcomas that you will encounter in the soft tissue um uh category U PSS, liposarcomas, myosarcomas and synovial sarcomas, they are all very different and behave very differently. Um U PSS for example, have a higher tumor mutational burdening burden. So, when thinking about novel therapies, we think about immunotherapy and what that, you know, the the influence of that it's more common. Um Leiomyosarcomas are um have a lower tumor mutational burden but they are mutated. Synovial sarcomas are often associated with gene translocations and liposarcomas are genetically very simple and very bland. But thinking about just taking one category, for example, and this is just illustrating. The complexity is that even within the title of liposarcoma liposarcoma is not one entity. There's well differentiated liposarcoma, dedifferentiated liposarcoma, myxo, round cell, sarcoma, pleomorphic, um liposarcoma, and all of these things look different down the microscope. So this is a historical side, looking at round cells and then looking um you can see the round cells at the bottom of this, this histology. And then this is a mixed with liposarcoma and you can also see the sort of fatty cells at the top of that slide. And then this is a scan looking at what things look like um sort of radiologically. So you can see that this is a CT scan of the abdomen of a patient. And here arrowed on the right is a dedifferentiated component of liposarcoma that looks very different to then the sort of the well differentiated component on the left here. And you can see that on CT scanning, they look very different. Um they're well differentiated compared to differentiated components. So I'll just remind you of this slide, thinking about your framework of how to approach your patients um with soft tissue sarcomas and what that means. So this is an ESMO guideline of, of how to treat this is for localized disease. We won't go into lots of detail but um welcome to have a, a quick look at this um uh slide but the take home messages is so the the orange boxes are surgical intervention and the green boxes are radiotherapy or chemotherapy intervention. And so this is for so you can get sort of get the idea that for lower grade tumors. So grade one tumors and for higher grade tumors, that surgery is a mainstay of treatment. But for higher grade tumors, we consider preoperative radiotherapy and or chemotherapy and that depends on the histological subtype, uh the size the symptoms, et cetera. Um There is also now a some tools that are available and I can actually, perhaps later, we can talk about this. Um If you wish there's some tools, things called like the SAR which are apps and tools that you can use to help to delineate whether your patient needs to have um postoperative chemotherapy. So that's thinking about localized disease. Now, thinking about metastatic disease which sadly, um of course, a large component of our patients if even if they don't present with um metastatic disease, develop meta metastatic disease later in their um course. So if there is an isolated metastases, if it is resectable, we always try to do c surgery. So it's oligo metastatic disease. Consider surgery always and thinking about whether the perioperative chemotherapy is necessary for advanced unresectable disease where people have multi site disease, which is not possible. Then anthracycline based chemotherapy is the mainstay of treatment. So with DOXOrubicin, typically, there are other chemotherapy drugs that we can add into the mix. And there was a big study um a few years ago, which looked at whether adding ifosfamide chemotherapy um would be of additional benefit to DOXOrubicin for patients with um soft tissue sarcomas. And the median overall survival was not improved. By addition of ifosfamide to DOXOrubicin, there was an improvement of of progression free survival. But what was noted in the study is that the combination of those two drugs is much more toxic and much more difficult to tolerate for patients. And so with no survival benefit. So we do consider the combination of doxorubin and ifosfamide for metastatic soft tissue sarcomas, but in fit patients and tend to be younger patients. And so it's very um patient specific choice. There's also now evidence um for first line treatment of addition of dox of dacarbazine with DOXOrubicin for leiomyosarcomas. So, just to see what can be achieved with um chemotherapy. Um so this is some examples of some first line um chemotherapy treatments outside of that. So, outside of the Anthracycline based um treatment. So, um this patient of mine had a angiosarcoma um which was uh locally aggressive but um not metastatic. Um you see of his head and neck. And on the left here is at the beginning of treatment and on the right is following six cycles of paclitaxel chemotherapy. So, angiosarcoma we know are sensitive to taxanes. And so the um first line treatment of choice is typically paclitaxel for these treatment for these tumor types. At the bottom. Here is a um a young patient um who presented with abdominal swelling and a absolutely enormous abdominal pelvic mass that you can see here on the left hand side. So the top um image is of his um CT scan and the bottom is of his pet scan. This was a desmoplastic small round cell tumor um which you may remember from one of the previous slides that's where they start in the abdominal cavity and the soft tissues. So, he had a combination of chemotherapy V DCI E. So this is vinCRIStine DOXOrubicin cyclophosphamide. And then two weeks later they get um ifosfamide and etoposide and then that those two are alternated every two weeks. And so this is following six cycles and you can see he's had an absolutely amazing response to treatment and um shrunk the disease right down and that, um that mass is, is much, much smaller and always imperceptible. So, second line treatment, um there are histologically specific um treatments that we can lean towards. Um And so this is some of the examples of that. So using high dose ifosfamide in de dedifferentiated liposarcoma, you can see that this mass in the abdomen at the top here has shrunk significantly after five cycles. Trabectidin is useful for mexide liposarcomas. So you can see this is a um uh a lump in this person's um thigh that has shrunk following 66 cycles. Um and gemcitabine and DOCEtaxel is also a common chemotherapy regime that we would use for soft tissue sarcomas. This is an example in Lear sarcoma following 33 cycles, you can see this lump has shrunk significantly. So those are some success stories with chemotherapy that I wanted to show you to see what is achievable that chemotherapy does work and can work. But of course, we know there are limitations to that treatment. Sometimes people have a primary resistance to chemotherapy. Um but and of course, much more commonly than people develop an acquired resistance to chemotherapy. Um there are certain subtypes of sarcomas that we know that don't, don't respond to chemotherapy at all. So, putting that into context, if we think about gastrointestinal stromal tumors, which I haven't focused on, um it's a whole other talk, but if we think that those tumors don't respond to chemotherapy at all. Um And so when that was the treatment sort of, you know, 2030 years ago, when targeted treatments weren't available, the outcomes for those patients were very different. But now in the advent, we know that a lot of those tumors have a specific kit mutation, which is sensitive to treatments with drugs like imatinib. And so they are now the back burner treatment and mainstay for those types of tumors um which has revolutionized the treatment of gastrointestinal stromal tumors. And there are other different sarcoma subtypes similarly that don't respond to chemotherapy like alveolar soft part sarcoma, for example. So here is um it's, it's don't worry about the details if you can't read them, but I guess this is an illustration of there has been a number of different targeted systemic treatments that have been trialed in soft tissue sarcomas, some with success, some without success. But these are the lists that have shown clinical activity in soft tissue sarcomas. Um However, this list actually has not entered or been approved in European countries and there are various reasons for that, of course, and not only getting through approval and in part, that can be the evidence base, but also the financial implications of these new targeted treatments. Sometimes these treatments however, can be available on compassionate access use um dependent of course on, on where you're um where you're based and where you're practicing. If that that is possible. Um then these treatments should be considered um obviously in balance with thinking about what your patient wants and shared decision making. Um radiotherapy in soft tissue sarcoma is definitely used in going back thinking about our framework of therapy and should definitely be considered for palliative cases where it's appropriate. And thinking about this. For example, if somebody has got a painful bone lesion, then palliative radiotherapy can be very helpful to help with pain. So I think important to mention because um in the sort of oncology sphere that immunotherapy is talked about a lot in lots of different cancer types. And I'm sure you know that of course, in in certain tumor types has been completely revolutionary for the treatment, for example, in Melanoma, um some lung cancers where immunotherapy is now FDA approved, ea approved nice, approved for use in those tumor types in the sarcoma world. Immunotherapy has not had such um striking success. And that's because historically, um sarcomas have been known to be immunologically quite quiet tumors with low mutational burdens. And we certainly know in the pediatric cohort that pediatric tumors. So that's the osteo um the ewing sarcomas rhabdomyosarcomas, we know that they have a lower mutational burden and therefore a much more difficult target for er immunotherapy. However, um with lots of research and clinical trials preclinically and um and clinically, we know that there are certain histological subtypes that are more immune hot. Um So the strategies that have been investigated are checkpoint blockade. So those are your things like CTLA four inhibitors PD one PD L1 inhibitors. Um um So that's ipilimumab is act LA four. I'm thinking about PD one and PDL one. We're talking about things like nivolumab, pembrolizumab aasi. So they have been tried in monotherapy, dual blockade in combination with local therapies like radiotherapy, um and isolated limb perfusion and also in combination with chemotherapy and T KS with success in certain subtypes. And we know that those subtypes that seem to respond better are U PSS, soft tissue sarcomas, synovial sarcomas and myxoid round cell. Um liposarcomas, another field which is very hot in um in oncology, research are adoptive cellular therapies. Um So things like engineered T cell therapies, car T cell therapies, um tumor infiltrated lymphocytes. So in hematological EMC car T cell therapy is now approved for use and just uh just at the end of last week. Um there was also some groundbreaking news that um tills are now approved for use in Melanoma also. Um So this is a, a very quickly evolving sphere. Um And in sarcoma, as I said in particularly soft tissue sarcoma is where more success has been seen. Um It's modest but there is some histological specific responses seen. Um the particular out outstanding um illustration of that is in alveolar soft part sarcoma, um that talizumab um produces some excellent durable responses. So, moving on to bone sarcomas. So um rarer as you know, fift about approximately 15% of all sarcomas are bone sarcomas. Keep in mind your framework because it's the approach is very helpful um with, with bone sarcomas also. And again, this is the ESMO guidelines for um treatment of um bone sarcomas. So, um if we focus for just a moment on the left side is osteosarcomas and differentiated between low grade and high grade tumors. Surgery isn't a backbone of treatment. Also in the bone sarcomas, the higher grade tumors. Um we also always give neoadjuvant treatment. So if you have a high grade resectable tumor localized disease, and you go across to this left hand side of this schema patients are treated with neoadjuvant chemotherapy, then they have their surgery and then they have more chemotherapy. The approach and reason to give chemotherapy upfront. So we're thinking about trying to shrink the tumor um to potentially facilitate a less extensive surgery. So whether it's possible to, for example, do limb sparing surgery rather than an amputation following neoadjuvant chemotherapy if there has been a good response. But also, of course, these patients are at high risk of metastatic spread. And so um the chemotherapy treats any potential micro metastatic disease upfront. Um And following surgery, they get more chemotherapy to consolidate that even patients with pulmonary metastases. Um those osteosarcoma um patients are treated with a similar intent. And if these, there are um if there is low burden isolated um lung metastases, then the approach is the same with an aim to do a meaty. So removal, surgical removal of those lung metastases following treatment. If disease is not resectable, widely metastatic a presentation, then patients are treated with chemotherapy and sometimes radiotherapy depending on the site and symptoms. Uh Ewing sarcoma is approached slightly differently. So for patients, whether they have localized disease or metastatic disease, for example, lung disease, they are treated with curative intent. So, neoadjuvant treatment, as I've just said, surgery followed by further chemotherapy and then in some selected cases, they get high dose chemotherapy and whole lung radiotherapy and all this is done with curative intent. So I think this is a helpful diagram to think about um who gets these tumors. And so I've already talked a little bit about, of course, the pediatric cohort and teenagers and things. But this is really helpful. I think um to remember the shapes of the curves when you are approaching patients and what's more likely that you occur. But of course, anything can happen at any time. So blue is the osteosarcoma. Um So this is age specific ratio. So this is the incidence according to age so you can see that the peak of osteosarcoma is in sort of late teenage and early adulthood. So this is the teenage and young adult cohort. So it's ty A we call it in UK, it's adolescents and young adults. So A Y A and those are the phrase that you'll hear and then incidence reduces, but there is a second peak in later life. So towards a later age into your sixties and seventies, then the incidence starts to increase. Again. The ewing sarcoma curve is the orange curve. So equally common in younger patients, the um increased instance in um teenagers and younger, it's in the ty a population, but then the curve drops off and there's although patients later in life can have those tumor types, there is not that in, in increased curve as for osteo chondrosarcomas increase um in instance, with increasing age. So that is much more in keeping with. So, you know, other tumor types, you know, that you would see commonly. So the older you get, the more likely you are to have a chondrosarcoma. So we're gonna talk about the most common um types um osteo and and Ewings in a bit more detail. So osteosarcoma is the most common primary bone tumor found in adolescents um affecting about 4.7 million Children and adolescents. Um it's the ninth um causes 9% sorry of cancer related deaths in Children. And as we said, there's a peak in later life. So the most common sites being your femur tibia and humera. So long bones. Yeah. Um the most common place for metastases is the lungs and also to other bone sites. And here you can see just histological um what things look like. So, osteoid is essential for osteosarcoma diagnosis at the bottom. Here is just an illustration of the subtypes of osteosarcoma. So even within this osteosarcoma diagnosis, there are other differentials. Um the most common and the high grade tumors being chondroblastic fibroblastic or osteoblastic um osteosarcomas. And that's the most common and the others are far rarer multimodality treatment. As we've talked about a lot already. Today, we give complex chemotherapy algorithms and local control and that's typically with surgery and potentially also radiotherapy as we talked about before. Um the importance of a, a multidisciplinary team and treatment within a Sarcoma center. And so, for patients to be cured, they need to have a multi modality approach and it requires complete surgical resection and chemotherapy. And so here, this is a study from um about almost 40 years ago um where at the time then sort of surgery um was the mainstay of treatment. And this was the first study that was done to look at whether adding chemotherapy in after your surgery made any difference. And you can see. So the bottom line is the um is the surgery alone and the top line is with chemotherapy. So, an incredible um improvement in relapse free survival for patients that have chemotherapy, postoperative. And so that's now um an absolute essential core part of treatment. So this was a study looking at um our, the treatments that we give and um whether any additional treatments would improve outcomes. So the important take home is that our standard of care treatment in the UK for um osteosarcoma is map. So that stands for methotrexate, DOXOrubicin and CISplatin. And so if you think back to what we talked about with the soft tissue sarcomas Anthracyclines, DOXOrubicin is a huge core component of treatments for sarcomas across the board. But with the addition of methotrexate and CISplatin in these in these patients. So methotrexate is given for patients that are under 40. If patients with osteosarcoma are diagnosed at over 40 they need to have map chemotherapy. We do not give the methotrexate, we give um ap so DOXOrubicin CISplatin. Um This study showed that was looking at the addition of other chemotherapy on top of map chemotherapy. If it made any difference of adding interferon or IE we've talked about before, but the results were not outstanding. And so the standard of care remains map chemotherapy as I've just alluded to you that older patients, they uh sadly have their prognosis is worse. Um because of the being um diagnosed at an older age is associated with um poorer outcomes. Um and there are still lots of questions in the sarcoma field about what should be the standard of care and what influences your decision making. Um And you can see actually on the right that the interestingly the um anatomical site of where um osteosarcomas start um is different depending on um age. And so um sort of breakdown there that it's that um often sort of more um overlapping or unspecified sites um slightly increased. Um pelvic bone sacrum and coccyx, which are very difficult sites, of course, for operations. If you think about the sorts of operations that are necessary in those pelvic um for pelvic tumors or spinal tumors. Whereas in the younger Children, those long bones osteosarcomas are more common like we talked about in the femur tibia humerus, um which has an influence on outcome patients with relapse disease, sadly have very poor outcomes. So following, if you relapse, following initial treatment, the key period is the two years following treatment. So if you have your patient who has undergone chemotherapy surgery, more chemotherapy, potentially radiotherapy those two years of follow up following that are very key. And we keep a very close eye on patients. And we know that if people relapse within that two year period, then their outcomes are far worse. The site of metastatic disease also has an influence. So if it's lung only that's better than other sites, but there's actually no standard of care treatment in this sphere. Um Our algorithm and the evidence and we know the active agents are ifosfamide and etoposide and that's what we, what we typically give in this, in this setting. So again, thinking about novel targeted agents of whether we know that of course, a huge amount of patients, despite having huge doses of very intense chemotherapy regimens that their, that their cancer can come back. And so always on the search for new treatments. And this is just an outline of some of the tyrosine kinase inhibitors that have been investigated in osteosarcoma. So you can see across the top the names of the studies. So I think the important things to take away from this is that if you look at the number of patients included in all of these studies, they are very small. Um So here, the biggest trial was 45 patients and that's the cab trial. So that was looking at a drug called Cabozantinib, which is a VEGF inhibitor, but also a a multi tyrosin kinase inhibitor. But these are very small numbers. And when you think about that in the context of cancer research and other trials and other tumor types that have potentially 100s or thousands of patients, you know, we have to in in these rare tumor types, we have to really consider numbers and thinking about it's difficult to recruit. And of course, it's a rarer tumor type. And so on the back of, of these studies, the sort of the agents with most evidence of efficacy were cabozantinib from the cab trial and also Rafen from the second line along there. And so those agents now actually are in investigation in other settings. And so there is a trial currently going on in the U looking at addition of tyrosine kinase upfront with alongside map chemotherapy, also thinking about maintenance options and things like that. So trying to reduce the risk of recurrence, if we continue an active agent following initial treatment, will that reduce the risk of recurrence in the UK? We have compassionate access to Cazin um and Regorafenib. So um we have to apply on an individual patient basis to have those drugs if we think it will be beneficial for them in the setting of of metastatic disease. So, ewing sarcoma um again, this is more common in the um as we looked at on our occurs, more common in the pediatric and tya cohort, these are small round blue cells and you can see that on the histologically side, um myology side on the right there, small blue round cells um histologically on I HC. They are C 99 positive and ewing sarcoma is characterized and diagnosed by a specific gene rearrangement. And that is the ew sr one gene. The most common translocation, as you can see on the right hand side table here is with the FL I one gene. So either one with the fly, one gene, that's the most common rearrangement seen in ewing sarcoma. There are other translocations that can be seen, but they are far rarer. But for a diagnosis of Ewing sarcoma, our histopathologists have to see that gene translocation. It's patho of ewing sarcoma. So it's, this is the second most common um tumor site. Um and this is looking at the um in, in young Children, in Children and teenagers. And this is just a little schemer to look at where ewing sarcoma primary sites can arise. So the most common being the pelvis and the chest wall. So it s like a different make up um to the osteosarcomas. The little pie chart here is looking at um patients that diagnosis where if they have got metastatic disease at diagnosis where the most common sites are. So 75% of patients don't have metastatic disease at at diagnosis, but then some patients do so, about 10% have lung metastases. Um 10% may have bone or bone marrow metastases and um 5% may have a combination of those. So, lung bone, bone marrow or other sites. Again, multi modality treatment, complex chemotherapy regimens, local treatment with surgery or radiotherapy. And patients in the Ewing sarcoma um population can be sort of stratified into risk groups. Um So, r one being localized disease R two being lung met only metastatic disease at diagnosis and then the higher risk highest risk group is um R three which is extra pulmonary metastases, bone and bone marrow. So, a big study was done um and was started about 10 years ago, the outcome of which has now given us a standard of care treatment that we use in the UK. So this was comparing V ID and V DCI E so very similar drugs but in a different combination. And again, this is complex chemotherapy regimens that we give. So this was a first line study randomized. Um and what this showed was that the comparing V with V DCI E um that V DCI E was um superior to vide. And so now that is our standard of care treatment and um to recap over what those drugs are. That's vinCRIStine, doxorubin and cyclophosphamide, ifosphamide and etoposide that are given in those alternating cycles every two weeks that we talked about earlier. So that's our standard of care treatment. V DCI. E again, relapse disease is really difficult and um long term survival if you have recurrent or relapsed, Ewings is very poor. And until recently, there was no um standard of care treatment for second line treatment in relapse disease. However, this study in fact is, is ongoing. But um the recur study is has been a sort of monumental trial in um Ewing sarcoma. And it was the first international randomized controlled trial looking at chemotherapy treatment for recurrent um and primary refracturing Ewing sarcoma. And there was multiple different treatment, arms looking at the different treatment, um potential treatments that we give were used to give in this, in this setting. So, um just so that I um tell you what these mean. So this is Gemcitabine and DOCEtaxel GD, um Irinotecan and Topotecan it um Temozolomide and cyclophosphamide ifosfamide. And so the overarching outcome from this is that, was that high dose ifosphamide is more effective at prolonging survival um than ah all the other options. So, um there is now an ongoing part of this study that's looking at other different agents like lenvatinib, which is another TK I and adding in um adding in other arms um including thinking about platinum treatment and things in this, in this um setting. But the takeaway for this is that second line for ewing sarcoma, that high dose of fosfamid has the best evidence. So I'm not going to go into detail about all of these different treatment. But I think hopefully just a helpful overview of thinking about um the next steps. And you know, we have chemotherapy and complex chemotherapy regimens, but they don't necessarily do the trick adequately for some of our patients. And especially in advanced disease, we need to keep thinking about targeted agents, immunotherapy, et cetera. So this is I think a nice diagram just to illustrate the strategies for targeted therapy about tyrosine kinase inhibitors, of course, but they can um target different parts of, of the molecular process. So the main um sort of focus is in thinking about the hallmarks of cancer um of what's target as angiogenesis, the cell cycle progression, sustained proliferation and signaling DNA repair, epigenetics and the tumor microenvironment. Um And so, as you can see, there are a large number of treatments that have been investigated in each of these domains and continue to be investigated to try to improve outcomes for our patients thinking about other future directions. Um I think helpful to note that um you, some of you may have heard of that um several years ago in the UK, we did a project called the 100,000 Genome Project. Um And that was looking, trying to sequence 100,000 genomes and it was successful. What came out of that was lots of different outcomes. Sarcoma perspective. Interestingly in that project, that sarcoma was one of the best recruited tumor types in the 100,000 genomes project, which I think is really fascinating considering its rarity and on the back of that and all of the information that can be gathered and the importance of molecularly profiling and genomically profiling these tumors. That whole genome sequencing is now approved in the UK for all new sarcoma diagnoses. The reason that it's important in this particular cohort is that um these tumors as we've talked about can be very difficult to diagnose. They can have very um although not, sometimes quiet, sometimes, not quiet immunological environments, but genomically can be very complicated. Um And so whole gene sequencing can do a number of things like they can help to guide diagnosis, can help to guide treatment, it can elucidate some germline mutations that patients had unknowingly. And with an ultimate aim, of course, for thinking about clinical trials and new treatments and helping these patients to have better outcomes. We've talked about oncogenic fusion proteins and particularly thinking about ewing sarcoma and the fusion that is diagnostic for Ewing sarcoma and trying to target those fusion proteins because there's also a number of others that have those immunotherapy strategies that we talked about thinking more about adopted cell therapies and how far we can go to improve those outcomes and then personalized precision medicine. This is very much a thing of the future. But I think aspirational and I hope interesting to think about what that really means and what that would look like and thinking about, of course, we want, ideally, there would be a wee drugs that would treat lots of different patients in and help to control their cancer, cure their cancer have durable responses. But then we know that in rarer tumors in particular, that's much more difficult to have those or encompassing treatments. And so thinking about personalized treatment and taking tumor cells from patients and undergoing next generation sequencing or whole genome sequencing. As I've just talked about drug screening to see what drugs work the best in your 3d cell models and then testing those in in vivo models to see if, if those treatments work. So um just to finish um the summary and I think, and some take home messages for you. So, sarcomas are very rare and they are heterogeneous tumors. Overall. Sadly, with a poor prognosis, the clinical presentation can be very diverse. Um and that commonly means that um misdiagnosis or delayed diagnosis is common can occur at any age. Um but is the most prevalent in pediatric and teenagers and young adults dependent on the histological subtype. Of course, if you have got a clinical concern about your patient having a sarcoma, it needs urgent investigation and think about that the, you know, your approach to that with imaging and biopsies. And then if available, um referring to a a Sarcoma specialist center, if you have access, conventional treatment is always almost always multimodality, surgery, chemotherapy, and radiotherapy. There is some history specific success of targeted therapies, my apologies that someone's phone ringing. Um and um if you have any issues um or you have a complicated case or anything like that, then think about discussing that in the international Sarcoma community. So there is a very, a relatively tight knit actually global sarcoma community. Um And if you have issues or cases on complex things that you want to talk about, think about um you know, asking your colleagues um because that happens to us all and there are various different discussion groups and tumor boards that happen. Um And if that's something that you're interested in, I'm sure that we can think about how to get details to you, the ones that are in existence and because it's always helpful for these rare cancers and complex cases to, to get, have discussion with your colleagues for help if, if it's warranted. Um So I think just in time um that's the end of my um my presentation. So, um thank you so much for listening. Um an hour's worth of um uh of sarcoma info. And so thanks for listening. And if you have any questions, very happy to answer them. Yeah. Well, firstly, I love that ring tone. That's just like I have to admit, I was like, sorry about that. Then I can see everyone loved the ring to. It was like, anyway, um please do put your questions in the chat. I told Eina that you guys asked lots and lots and lots of questions. So thank you for asking yours. But please pop your questions in the chat. So ashe asked, do you undertake staging in Sarcomas similar to other forms I etn Yes, great question. So, um yes, we do. And so um if we think back to um right at the beginning, um I guess I could probably actually go back if you want to say. But um yes, part of staging is with TNM staging. So that's of course, tumor staging. Um So grade and stage of your tumor. Um But also T and M staging. So there is different TNM staging dependent on the histological subtype of sarcoma. Um And so, um so, depending on whether it's a bone tumor or a soft tissue tumor or a gyne tumor or a gastrointestinal stromal tumor. Um and the extent of, of all of those things. But yes, we do do TNM staging. And so to achieve that all patients, you need to have a CT staging scan. Um is the, is the primary source of getting that information, of course. And along with histological um staging also. Perfect. Well, just in case someone's writing a really long question, I'm gonna take you up a few levels of uh knowledge, cos I have no knowledge. But you started off by saying about 1% of all cancers are sarcomas. Have you seen, you know, like our cancer rating? It's now one in two who get cancer. Have you seen then the sarcoma increase in that as well or not? It's a really good question. So interestingly, we have definitely. So um in our center seen an increase in an enormous increase in referrals, but there has also been an increase in diagnoses. So what is interesting about that is that I think that there's still lots of work to be done to know quite what that, where that, where that's coming from, where that rise is coming from. Because um these are not cancers, for example, like lung cancers where you can say there is an association with something like smoking and you say, well, if more people smoke, then more people get these types of tumors, it's there are less clear cut sort of oncogenic drivers, um um externally in sarcomas. Um we know there are certain germline mutations. So things that you inherit from your mom and dad, like ap 53 mutation, which is associated with Lee Fraumeni syndrome. And we know that that makes you more likely and more at risk of various different cancers including sarcomas. But of course, those kind of germline mutations don't, they're inherited in families and those don't necessarily increase in instance. So I think that we have it's, it's very interesting perhaps it's also because um hopefully lots of education is happening. Um And so, um trying to reduce those sad cases where patients are diagnosed misdiagnosed or diagnosed late. And so we're seeing the the the incidence and the increasing earlier earlier on in the treatment journey. Um potentially. Um but yeah, it's a very good, I think it's probably, it's probably altering in a different way to other different tumor types. Um But yeah, it's, it's still a an area to look into for sure. So I need to say hello, we are professional. Honestly. You also said I have a question here and I'll get to that one, but you also said at the beginning about 20 ce 20% of of your patients are pediatric, are Children. Yeah. So why doesn't an adult get it so much as a child gets it, it happens in like I said, I'm not medical at all. It happens in a child's body that gives them that, that then goes the later the older they are. So, um so that was actually, so what that was me is that sort of out of, out of all pediatric cancers, about 20% of pediatric cancers are sarcomas. So, um obviously the, as you, as you have said to the kind of um the make up of cancer types are completely different in Children compared to adults. And so they tend to get hematological malignancies, you know, like leukemias, et cetera, and sarcomas like osteosarcomas, ewing sarcomas, whereas in an older age, it's more, more typically cancers related to um perhaps environmental factors or other health factors, et cetera. And so there is a very different sort of pathogenesis and um we're not necessarily talking about external sort of um oncogenic hits. And so you think back, back to that slide, right at the beginning when you thinking about your stem cells and how they are affected by potential oncogenic insults, and they um equally, that's why pediatric tumors are much more sort of much less genetically complicated. They can tend to have one driver mutation. So thinking about the ewing sarcomas, they've got a fusion gene that is um abnormal and that one fusion gene is what's driving that cancer to grow. Um sometimes that is related to, you know, a germ eye mutation as I've just said that they've inherited from mum and dad, um or sometimes it's it's not, you know, it's, it's somatic and actually the, the, you know, there's not germ eye mutations associated with those genotypes are still quite small. But of course, that's more likely in a younger population. Yeah. So sad, isn't it? You know, cancer is awful anyway. But if it's Children as well anyway, I am going to add another question. Oh, sorry, it, not that one next question. Here we go. If sarcoma is malignant, how do you differentiate it from carcinoma? Great, good question. So, um the way to do that is histologically. And so there are if you think about the different components of what things look like down the microscope when you've done your biopsy. So um carcinoma cells and sort of uh those connective tissue cells can look different. So morphological appearance is important. Um and if we heart back thinking back to what we've just had a look at some of those histological slides that for example, Ewing's small blue round cell tumors, you know, that's a distinct entity and looks very different to a carcinoma. So, morphologically they look different immunohistochemistry can help us. So, looking at certain cell surface markers dependent on the tumor type, that's um and there of course are standard panels that would be positive in carcinomas um and not positive in sarcomas. Um And then moving on, thinking about genomic sequencing. So um thinking about if you N GS panels, so panels of different cell um genetic alterations that can be done to try and elucidate diagnosis as well. There are some cases that can be difficult to differentiate, especially if you're thinking about an undifferentiated cancer. And so, you know, some that have not altered, um you are not very well differentiated. Um it can be complex trying to delineate between whether this is a sarcoma carcinoma, but you use those things to guide you. So, morphology, immunohistochemistry, next generation sequencing, we now also use whole genome sequencing. But all of those things put together the picture of differentiating sort of mesenchymal from epithelial cell origin. Wow. Wow. And thank goodness for technology that it has, you know, moved on so much, you know, I know there's more, you know, we hear about it more or cancer and, but thank goodness for treatments evolving, you know, and research evolving and you know, it is something that is becoming more and more, the other cancers are more and more curable. I'm assuming then sarcomas will be more and more curable in the future. That's the hope. Obviously. Exactly. I think we're just a little bit behind. I think that's what you know, and I think there is a lot of hope. Yeah, exactly that we can come to a phase where some of our patients are cured. You know, there's no and there are some success stories. So it's not all doom and gloom. But I think, you know, as you said, there's still lots of scope for those patients that sadly don't have are not cured. There's lots of scope to improve outcomes for them. Yeah. Um, we have just a follow up that I've just popped up on the, regardless of sarcoma or carcinoma would treatment be the same. Um, no, is the short answer. So, um I think where this is, so if you're thinking about extremities, it's less likely. But if you're thinking about anatomical sites where um this is gonna be particularly relevant. So if you're thinking about a gyne sarcoma, for example, and so, of course, so they're arising from the gynae tract, these tumors, but you can have um of course, carcinomas are, are typical to epithelial tumors in the gy tract are common. So, ovarian cancers, endometrial, um cancers, et cetera. Um they are staged in the same way, but their cell of origin is different to those that can come from a sarcoma. So a mesenchymal background, for example, a leiomyosarcoma um or an adenosarcoma or of course, an entity that is a carcinosarcoma, which can be very um which obviously is um makes it complicated thinking about what that means and the difference, but the treatments are different. So it's really important to make that differentiation. So, thinking about ovarian cancers, for example, um of course surgery, an important mainstay of treatment just the same, but the drugs that are given are very different. So that's the the the chemotherapy regimen. So thinking about a ovarian epithelial tumor things like um platinums and taxanes are given. So, carboplatin paclitaxel are a mainstay of treatment. Whereas for sarcomas of the gynae tract, we would give more anthracycline based treatment, DOXOrubicin, dacarbazine, IOS. Um But I think always important. So when you're thinking about any, any cancer patient, um you know, I showed you that sort of conventional sarcoma treatment guide, but that's also a guide for oncology management as a whole thinking about if an operation is possible to get this disease out, then that then do that. Um And then the other treatments are more tailored um to the histological type. I'm sorry, I now have a question, another question based on what you just said, sorry. So if you gave treatment, so you were saying about um I think it was, I can't remember if it was ovarian cancer or whatever. If you, you need the wrong treatment. If you gave the treatment to cancer for cancer rather than the sarcoma, would that make? And it was a sarcoma, would that make the sarcoma worse? Would it do anything at all or what does it do? Sure. Yeah. Really good question. So, um we know that different chemotherapies work differently in different tumor types. And so the evidence based so it basically probably wouldn't work. So if you gave the chemotherapy that you would typically give to an ovarian cancer to someone who actually had a sarcoma from the ovary, then the, the chemotherapy wouldn't work. It wouldn't help to shrink the tumor and it wouldn't, it wouldn't make it worse, but it would not help for it to get better and therefore the tumors may grow. Yeah. And then it might get to the point where treatment isn't a possibility. And, ok, perfect. Well, not perfect. But thank you very much. Exactly. And so important to delineate as you're able. But that can be very difficult. And I think, you know, I'm not, I'm a pathologist but we have lots of conversations in our MDT S about complex cases that are difficult to diagnose. And that's why we're lucky that we've got availability of next generation sequencing and genomics to help us to delineate that. But immunohistochemistry can also be very valuable. Uh So you said you're very lucky that you have uh the long words that you mentioned. So does that mean that's not available in a lot of countries? And they would have to do the other long word you said? So, um I think it would be actually, I mean, I don't know if anybody wants it, it would be really interested. I think it's really important and interesting to think about what is available um across the globe. Um And, you know, there are certain things that are more standard and, and other things that are not. Um And I think, you know, in part of course, because a lot of these um ways of investigating, um it's, as you said, it's very high tech stuff and it's very expensive. Um, and so, um, I think that it would be interesting actually to, to hear that, I don't know if it's possible from people attending of what is available in each center. But I think, you know, you've got to just use what you've got and like, there is no, you know, if, if you're working in a center that doesn't have access to certain things that using the more, you know, sort of morphology and what the cells look like under the microscope or immunohistochemistry, which is more widely available. If you have got other molecular or genomic testing, then then great utilize it. Um um But I recognize that that is not necessarily possible. Um you know, in different countries. Perfect. Well, I think there's no one else who's asked any questions. I think I have asked you loops. Um So if everyone is happy, what we'll do, you'll get your feedback form if you can fill that out. Really, a lot of the feedback is for Regina about her presentation about the content context, that kind of thing, our consultants that come and speak on me education, this is something that they take away with them to learn for their growth. Um So please do fill out the feedback form and once you've completed it, you will get your attendance certificate and I will be passing all that feedback onto Georgina. And I have my fingers crossed that she might do some more teaching for us uh at another point. So, um I'm gonna say goodbye to all our delegates and thank you very much for joining us and we'll see you on another medal education event. Um And that's us done for me education. Thank you very much.