UCSF specialists report from the front lines of treatment for neuroendocrine tumors, pancreatic cancer and sarcomas. This three-part video covers:
An update on classifying NETs, who’s a candidate for resection, the latest drugs for NETs (including peptide receptor radionuclide therapy) and how to time treatment
Why pancreatic cancer is common and aggressive, a look at the FOLFIRINOX regimen, whether “chemo holidays” are safe, and new guidelines on germline testing and tumor analysis
Why multidisciplinary collaboration is essential to treating sarcomas, how surgical creativity can preserve function, and a look at using a 3D model to plan a complicated surgery
Hello everyone and welcome to cancer center live our series of CMI and educational virtual events. Uh This is our second year of actually doing these conferences and we're really excited tonight for our last session of this fiscal year. Um Tonight we have a great topics and speakers, we're gonna be talking about less common tumors but equally important we have Emily Berglund who is going to be talking about the latest advances and work up classification and treatment, gastro intro but pancreatic neuroendocrine tumors. Um And she's in the has the Ernie Rosenbaum endowed Chair in Medical Oncology um and director of the UCSF Center for neuro endocrine tumors here at the Comprehensive Cancer Center at UCSF. But then we'll have time for A Q. And A. After each talk. But then we'll hear from Margaret tempo, the director of the UCSF pancreas Center and chair of the national Comprehensive Cancer Network guideline Panel for pancreatic cancer as well as the editor in chief of JN CCN Journal as I think many have you have seen and read, she's going to talk to us about updates and the management of pancreatic cancer. And then our last but not least, speaker is Rosanna West Track, she's an associate professor of clinical orthopedic surgery and the chief of musculoskeletal oncology uh and tremendous resource for all of us at the Cancer center and she's going to talk about surgical management of sarcoma on your screen, you'll see at the bottom. There's a Q. And a icon. If you when you have questions, comments, anything a question about a case. Anything that comes up, please put them into the Q and a box and we'll be able to answer those lives and if we don't get to them, we can answer them online. We have the chat box if you have any trouble with your connection but otherwise do use the Q and a box for questions as they come up. Don't wait till the end during our talks. And then uh this will be recorded and will be posted on the cancer center website and we can send you the link in the chat as we go through this session. Um and also we usually have the link at the end. I'm not sure if we do this time, but I think that these sessions are really for all of you, so definitely participate and ask questions as we go through with our expert speakers. I'm hope rubio breast medical oncologist at UCSF. I and I'm joined by Laura Criscito, who is the director of this program um and will speak to you more about the program in the future and her own role. Good evening everyone and welcome. So I'm laura Crecido CMO and VP of cancer services at UCSF and welcome to our Cancer center live series. This is the fourth program we've had in this fiscal year. Um we look forward to doing this again next year. Please feel free to put in the chat or email us after any ideas or suggestions that you have for topics that would be of interest to you. Um really, as dr rubio mentioned, this is for you. And so we want to make sure that we're providing you the information that you want and we have lots of expertise at UCSF to share. Um so welcome. And I think the next slide is our disclosures and then we'll start with dr birds land. Thanks very much. So, Emily you're on okay. All right. All right, great. Well thank you so much for the opportunity to speak today. So as mentioned, I'm going to be talking about the World Cup classification and treatment of advanced G. I. And pancreatic neuroendocrine tumors, also known as get millions. Um and I want to just highlight that just to lay the foundation here that neuro endocrine ectoplasm can arise nearly anywhere in the body. They can be high or low grade and for the sake of time today I'm just going to be focused on the ones arising in the G. I. Track and pancreas. But I will try to touch on the high grade tumors of these sites as well because we're definitely seeing those on a regular basis. So in terms of the genetics of the low grade tumors, most of these are sporadic. Um only 10% are associated with the familial syndrome, with the most common one being M. E. N. One. But I also just wanted to highlight that there's some new data over the last few years that patients with pancreatic neuroendocrine tumors Have a higher risk of a germ line alteration, there's a couple of papers that suggest about 17% have a germ line alteration. And while this includes things like M. E. N. One and T. S. C. And V. H. L. It also includes the about 1 to 2% bracket to also check to mute Yh. So we have very low threshold for referring people for genetic testing and at the very least take a good family history in terms of what the ties all of these together is that they typically will express neuroendocrine markers. The low grade tumors will be positive on this for Samantha statin receptor expression by imaging. Uh We've really switched away from the old Samantha statin cinematography too. Dota Tate pet imaging either with copper 64 gallium 68. Um And they're characterized by site of origin ability to make peptides that cause syndromes and then the histological grade and differentiation. And just a reminder about the classification system. This has been evolving. It's actually changed a couple of times over the last 10 years and I want to highlight that in 2017, a new category was added which is for well differentiated tumors which have a K. I. 67 proliferation index greater than 20%. Um And this then is another category of high grade disease which is separate from poorly differentiated neuroendocrine carcinomas And then in 2019. Um when while this was first identified in the pancreatic tumors in 2019 this was extended to G. I. tumors as well. So what we have is sort of shown here where on the one end of the spectrum we have the very poorly differentiated um high grade high case 67 uh carcinomas. These often have but not always have RB alterations or P 53 alterations. Their positive on F. D. G. Pet and typically would be negative or weakly positive on Dota pet. And then the other end of the spectrum we have the well differentiated neuroendocrine tumors with the Grade one and two tumors having A. K. I 67 less than 3% and 20% respectively. Um And those in the pancreas anyway are typically characterized by M. E. N. One A. TRX or dax alterations with the G. I. Ones not not having a lot of common alterations. And then in the middle we have this new category of well different G. Dealt well differentiated G. Three net which can overlap in terms of the clinical characteristics and imaging characteristics. So the key takeaways um is that you really need both. You need the the proliferation rate. Um either metabolic rate or K. 67 plus differentiation to classify these tumors. G1 tumors by definition are well differentiated but G3 can be well or poorly differentiated and it's important to note that there can be quite a bit of ambiguity in the history pathologic features and it can be difficult for pathologists to actually agree on whether it's well or poorly differentiated. So one thing to keep in mind is this this difficulty making the correct diagnosis but also to re biopsy. If the patient's clinical course doesn't fit with the biopsy results, you have on hand recognizing that it can change over time. And this has now been uh Reported in a number of publications and pancreas tumors in particular where the KII 67 can increase over time and there can be a grade change, even converting to high grade in some patients. So talking about treatment now, I want to focus on the low grade G 12 nets first. Um Again, these are they're uncommon by incidents. But if you look at prevalence, these account for 10% of pancreatic tumors, uh they're usually well differentiated. The most common site for the weld. If G three is actually in the pancreas, I mentioned the recurring somatic mutations. Um overall the prognosis is pretty good in the metastatic setting. It's over five years. Um and I will just mention, but won't talk about it much today. This this entity of just small nets that are not metastatic. That is an increasing problem that will usually just watch on imaging unless they're over two cm. Most of these are non functional, but of course some of them will make hormones like gastric and insulin. Um Now for the extra pancreatic neuroendocrine tumors. they've historically been divided by as forgot mid gutter hind gut. These used to be called carcinoid tumors, but we've moved away from that technology. The terminology. Um, most of these are non functional, but the classic site for carcinoid syndrome would be illegal tumors in the small bowel in the, in the forgot. We sometimes also see cushing's. And again, recurring mutations are pretty rare in this population. So if we have metastatic disease, the first thing we look at is whether resection is possible and if we can do bulk, the majority of the disease, meaning 70-90% will consider this in a fit person, often with the primary um at the same time or or a separate surgery. The one caveat being pancreas head tumors that require whipple. That's a very a difficult situation and requires a lot of discussion before proceeding to resection. And the reason is because this is a palliative operation. Unlike colon cancer where we cure patients with resection, uh the data suggests that this really just sets the clock back and the recurrence rate by 10 years is about is close to 100%. So that needs to be considered when deciding in whom you might consider de bulking for unrestricted disease. There are two main indications for therapy. One would be somebody who's got hormone mediated symptoms or pain from bulky tumor. And the other is the person with with clearly progressive disease. Short of that, if it's incidentally discovered tumor, you could watch and observe with serial scans before instituting therapy. Um Now there have been a lot of drug approvals over the last few years um that have really expanded our armamentarium for patients and I'll go over most of these um in the upcoming slides. I would also just mention that we use a lot of liver directed therapy for which we don't have level one data, but we've been using that for the for years and continue to integrate that into our treatment algorithms. So, and the reason liver directed therapy is so powerful, it's one of the things that actually causes shrinkage with shrinkage and about 50% of patients, we don't have randomized data to the guide choice of anabolic technique, whether it's uh land or with chemo or radio labeled beads. You have to be careful with these procedures and patients with the prior ripple due to the concern for abscess. And I would say we use why 90 radiation therapy much less commonly than regular embolization. Just because most of these patients will go on to get radio radiation therapy in the form of peptide receptor radio nuke light therapy. And there's a sweet spot for doing liver directed therapy when there's somewhere between around 10-70% liver involvements. You don't want to do it too soon or too late. But you also want to be aware of the possibility of delayed him beto toxicity and you know we use it judiciously with some of our patients having a few of these cases before we go on to other treatments. But given that we have other agents to use we want to be careful to not over treat um with many many liver directed procedures. Um Samantha Staten analogs of course are the really the workhorse of treatment at least. Initial treatment for patients with well differentiated tumors. Both factory a tight and Landry a tide delayed tumor progression. And both of them have data suggesting that they control they control hormone mediated symptoms technically land real tight is approved for both indications and altria tights just to prove for symptom control. But in practice we really use these interchangeably in clinic. And then I just wanted to highlight there there are some new data that suggests a role for above labeled labeled dozing that also may delay progression in patients who previously failed lower dose. Um It's not FDA approved and we use it sparingly. But I just wanted to highlight that as you'll see this come up in the next um in the next slide which relates to Pr. T. So P. R. T. Stands for peptide receptor radionuclide therapy. And um this was FDA approved based on the net er one phase three trial which was a trial in mid gut tumors that had progressed on standard dose solectria tied patients received four doses of this agent which basically takes a semana stand in analog and calculates it with the radionuclide to provide targeted radiation based on Samantha statin receptor expression Patients had four doses intravenously over a six-month period to give the doses every eight weeks. And here's where you can see the control arm was double dose um Victory a tight L. A. R. At 60 mg every four weeks. And here are the data on the left. You'll see the primary endpoint of progression free survival. A really profound improvement in progression free survival hazard ratio 0.21 median progression free survival is is close to 30 months with the P. R. T. Response rates pretty low. Only about 15% in mid gut tumors but again profound improvement in PFS. There was a trend towards improved overall survival. But I would just point out that many of the patients initially who were assigned to control arm ultimately went on to get pr t later on. And this was approved um about three years ago. And now interestingly the approval was for both G. I. And pancreas. And you might wonder why did pancreas get approved because it wasn't part of the Phase three study. But basically the F. D. A. Considered retrospective data from the Netherlands and close to 400 patients for whom they had resist data. Again the overall response rate was low is around 15%. But it was enough to convince the FDA that again in selected patients with metastatic receptor expression. Uh This this drug had activity. I will also say that retrospective retrospective data suggests a higher response rate in pancreatic neuroendocrine tumors up to 50% in some studies. But that hasn't been confirmed in prospective studies. It's a pretty well tolerated drug but the main side effect being Milosz oppression, which is why you space out the treatment's over um two months and you have to do it in patients with adequate renal function. Um But one of the adverse events just to be aware of is the risk of delayed um onset myelodysplastic syndrome in leukemia, which happens in somewhere between two and 3 to 2 to 3% of patients at 2 to 4 years. And this is why we don't typically use it widely upfront right out of the gates. But instead we start with regular Samantha statin analog and sort of work our way through the algorithm before we get to Pr T. Now, I also want to point out something important which is that here's a whole range of Dota scans in patients Dota Tate pet scans. I just want to highlight that just because somebody has a positive skin, it's the right time for P. R. T. And you know, some patients on here, you might look at and think, you know like the far right patient, you know, really really potentially appropriate person for PR T if they've um progressed on the simvastatin analog and some of the others might be appropriate to. But you could you might imagine some of them might benefit from liver directed therapy. Um potentially before PR T. Some of them might even benefit from surgery um resection. And then I also want to highlight that on that far left panel. Beware of the report that calls out a positive Dota scan that's not really positive meaning a good person for PR. T. Because we want to look for uptake that's greater than than the liver background and this particular patient it's it's window a little funny but the point is that the thematic tumor had week Dota uptake but it's less than the background in the liver. So this is a one of the first patients I referred for P. R. T. And it was a learning experience for me that it wasn't enough uptake to actually merit PR. T. Um So just be aware of that. Make sure you look at the scans yourself and you want to make sure you're seeing strong uptake relative to the liver. Now, systemic chemotherapy does have a role in um Gap nets mainly in the pancreas where striptease. Ocean based therapy has really been replaced by Capeside tambien Te Mazzola might therapy based on peacock 20 to 11 which showed that Cape TEM was associated with a longer PFS than to Mazola might alone. Um We rarely use chemotherapy for the extra pancreatic nets. Although we do sometimes but again response rates are pretty low in terms of targeted agents. Um Ever dilemmas is approved in G. I. And lung nets based on the radiant for data. You can see a prolongation in median PFS although the response rates are quite low. So again a sight a static agent and ever Olympus has also approved for pancreatic neuroendocrine tumors. As is Senator nina. Um I want I'm showing you data from different phase three trials just to show you in a cross trial comparison that they are pretty similar in terms of their actions. So you know these are sight a static agents. They delay progression. Response rate is low. Both of these are approved in pancreatic neuroendocrine tumors. So you have to sort of um select between the two based on other clinical features come abilities etcetera and they can be used sequentially certainly. Um Now I just wanted to highlight that sarafina biz, another veg F. T. K. I. Which is under study. Uh It's already approved in china based on the two phase three studies that I show you on the right with delayed progression free survival and it's currently under review in the United States. So we have a variety of agents available for well differentiated neuroendocrine tumors. Most of them are cited static delaying progression without major shrinkage. Um Some of them do cause shrinkage though. And our goal when certainly when I see somebody in clinic is that they have access to all of these at some point during their disease But that we have to choose wisely and there is really no right or wrong way to do this in patients. But we include two more factors like the KII 67 the burden of disease, the patient, um the rate of growth, whether the portal vein is patent, for example, the primary site we look at the patient and their comorbidities, their prior therapy, um their goals of therapy, you know, they have really bulky disease and need shrinkage or is it small volume disease. And then of course we look at you know provided a preference and access to care. But the take home message certainly for our group is that it's very multidisciplinary and we have a tumor board that meets every other week and we review lots and lots of cases to really address this exact question, which is how to sequence these. So um I just want to point out that there still are a lot of questions, you know, as I mentioned in the first line setting typically will use line real tight or Austria tied for gi neuroendocrine in the second line and beyond will use liver directed therapy. P. R. T. And never dilemmas. But lots of questions remain. Such as the use of Samantha Staten monologues when the K- 67 is higher. That hasn't been tested in the previous Studies. So over 10% is still a matter of debate. Um how can we optimize pr T um are there other agents we can use, how do we sequence these as I mentioned and then treatment of refractory disease and then similarly for pancreas tumors. We have more treatment options as I mentioned chemotherapy and soon it nib are used more widely in this disease. But very similar questions about how to sequence and select therapy. Uh The role of P. R. T. As I said hasn't been actually tested prospectively in randomized studies and then treatment of refractory disease and a lot of these are now under study. So I won't go through this in in detail but there are studies looking at different ways to dose PRT. So using the symmetry for example rather than a flat dose there are studies with new radio labeled peptides with alpha emitters being quite popular right now as as a new uh new type of radionuclide to use. And then there's pr T. Versus other available therapies. Many studies are now comparing P. R. T. To chemotherapy, comparing it to um targeted agents. There are studies looking at P. R. T. And bronchial net which again is unstudied so far. And so lots of I think important data that will be coming in over the next few years to inform our practice. And then finally just to mention of the cabinet study this is open here which is looking at cabins Santana versus placebo with crossover. And there are two cohorts a pancreas as well as an extra pancreatic cohort. So in my last few minutes just gonna briefly touch on high grade neuroendocrine neo plasm. Again just a reminder that um the high grade category now includes G. Three neuro endocrine tumors that are well differentiated as well as poorly differentiated neuroendocrine carcinomas. Both small and large cell types. And then um to make it more complicated there's a mixed subtype called mixed neuro endocrine, non neuroendocrine neo plasm. Um Those happen not that commonly because we often don't get the whole tumor out to see if it's mixed but um they're suspected to occur and potentially up to 30% of high grade disease. And I just showed you an example on the bottom right of an H. And E. As well as a synaptic spice and stain. We're on the right. You can see the adenocarcinoma component is really right adjacent to the neuro endocrine component which is the only synaptic vice and staining component. So um very briefly for G. Three neuro endocrine tumors. I really kind of base it based on my sense of the biology. So cross sectional imaging if it's a lower K. I. 67 favorable biology and I can only choose one pet scan. I'll do a Dota scan Again I've seen K. 67 is over 70% in well differentiated tumor. So I might prefer to do it f G in some cases basic labs and then the role of mutation profiling is unclear but I have a low threshold for doing it in G. Three. And again we're looking for something that might be actionable. I've had a few entrapped fusions and occasional M. S. I. Hi. But um and the other reason I do it is if I see an A. TRX or dax around me and one mutation that really does suggest a well differentiated tumor pathology review is important. I mentioned that this cannot there can often be ambiguity and I treat it either like a low grade or a poorly differentiated neo plasm depending on the biology and the other features in contrast for the neuroendocrine carcinomas, if we do a pet at all, we usually go to F. D. G. Pet, we don't typically do Dota Pet. Um We will sometimes do brain M. R. I think brain disease is less common in the outside of the lungs. But we we will occasionally do that. I like lDH to get a sense of the burden of the disease and to follow as a marker low threshold for mutation profiling. There's some data that about 4 to 5% of patients will have high TMB or M. S. I. High. So it's definitely worth in my view, making sure you've ruled those out and then typically platinum based chemotherapy first line. Um So again to highlight the algorithm um high grade, poorly differentiated, you know, bad biology RB alteration FTD positive. We put on platinum atop aside no really good salvage therapy. I mean all the chemotherapies have a response rate typically on the order of 10 to 15%. There's a little bit of data within the Nevo. I'll show you in a moment but definite need for more agents there for the well differentiated tumors. Especially as I said, there's an M. E. N. One A. TRX dax alteration. It's Dota avid. You know, I will treat it variably like higher low grade, depending on the on the on the behavior and then just keep your eye out for ambiguous because the the sort of incidents of this varies from paper to paper. We have found a lot of ambiguous cases in our own review of data here and again, how I treat that really depends on the clinical setting and I will sometimes just go ahead and give a couple of cycles of platinum isotope aside, if I'm unsure and I can't rule out the possibility of a poorly differentiated neo plasm. So, um, last couple of slides on P. R. T. For A G. Three disease. We don't typically do it. We know by and large these patients have a worse prognosis than the low grade tumors. Um, the response rate isn't bad. It's about 40% in either G three net or neck. It's just not as durable as what you see in the low grade tumors. So we don't typically use pR T in outside of a research setting unless it's G three net With favorable biology and low grade, low relatively located 67 meaning like in that 20-40% range um immunotherapy so far has been a bit of a bus Single agent therapy has not been effective in these extra pulmonary neuroendocrine combination therapies. There's now a few published studies. I've listed them here. They're pretty small. They're mostly around 30 patients per cohort. But the response rates ranged from 9-25% in these very mixed cohorts. And it has made it to the n. c. c. n. guidelines for G. three disease. So I just wanted to highlight that and then of course there are a number of combinations studies that are underway. I wanted to highlight one at UCSF we have a pet brutalism add plus liver directed therapy or P. R. T. And we are enrolling R. G. Three net patients to that PRT pembroke component. And then nationally there's a platinum top aside plus or minus tezo for patients with extra pulmonary small cell. And this is really great because it asked that question of what's the role of first line immunotherapy in these patients. So to end I just want to say no what you're treating. Um you know I think talk to the pathologist if you have any questions keep in mind that the biology can change over time and re biopsy if it's clinically indicated For G. one and 2 tumors. Remember it's a marathon not a sprint. These people can live many years and sometimes decades. And so we want to dole out that therapy very judiciously over their disease continuum. The clinical picture dictates therapy for G three nets. The treatment for poorly differentiated neck is really problematic right now, definitely encourage enrollment to clinical trials. Um and I will just end by saying that we have a website if you want more information about the disease or what we can provide here. If you have any questions. My email is listed below and I'm happy to take any questions if there's time now or later and I can look at it in the chat. Wonderful. Thank you so much. That was such a great talk and I learned a huge amount. Uh really great. So we have a I think time for a couple of questions here. So uh Nita Lennon asks, what is your take on pituitary nets and how would you treat them differently? And I think as an extension to that question for me is you know, how do you we've seen neuro endocrine tumors in the breast all the time, but we don't treat them this way. So how does the cell of origin really determine how you're treating these cancers? Those are great questions. So in answer. So the first question that is a really rare tumor type and I have to say I do not treat those. I think when I think I've had maybe one of these sent my way over the last few years and we've referred them to neuro oncology. So I would say for that one, I don't I think it's completely unknown. Um not a lot that I know about it and I would say have neuro on take a look in terms of your question about um site of origin. I would just make 11 point first. And that is beware of the tumors with neuro endocrine features and not true neuroendocrine carcinomas. And I know I hope you and I have shared a lot of patients over the years like this. Um it's pretty common if you're if you stay in 100 adenocarcinoma as with neuro endocrine markers, you'll get some neuro endocrine staining that's different than being a true neuroendocrine carcinoma. So that's that's number one and that's why we often will treat it. Like if it's a breast carcinoma with neuroendocrine features, we usually treat it like breast cancer in terms of tailoring the therapy to site of origin though, I think comes up a lot in G Three disease. For example, in in colon neuroendocrine carcinomas, they often have a pc wrasse p 53 mutations very similar to colon cancer and as I mentioned many of these tumors, if you were to actually get the whole tumor out, you would find they have an adenoma or squamous component and it's an unanswered question whether chemotherapeutic agents used for the non enter consumers of that site should be used in this disease or not. But I will say that's what I use. So if I have a colon cancer patient, neuro endocrine patient that fails platinum atop aside, I will often use full fox or full fury in the second line setting. Um, and ditto for any other tumor types. But I will tell you mayo had a really nice review of this a few years ago. And honestly any second line therapy. The response rates are 10 to 15%. And it, I don't think we've found out how to actually select therapy. And then the last question, this peptide receptor radionuclide therapy is really interesting. Um, is there any other ways that are being evaluated? You know, antibody drug contradicts are all the rage now. Is there a way to do radionuclide delivery in any other mechanism and why do you not use it for higher grade nasty or tumors? That's because it's not effective enough. I mean, you you need to give it with chemo sequencing it with chemo for those nasty rumors. Yeah. So I think it's, you know, it's relatively early days for the field. It was just approved in 2018. So people are playing around with different radio peptides. Um, uh, you know, different dozing strategies. The combinations with chemotherapy. The Australians have published on this. The risk of MDS goes way up. Um, it was over 5.5% with the Mazola meat combined. And I think there's a lot of concern when you start doing combination therapy. Clearly PRT is being looked at in other diseases by the way, as people probably know like prostate and others. So I think this whole field is blossoming looking at different radio peptides in terms of antibody based strategies. There are some of those coming down the pipeline, certainly like different types of convenience, not necessarily radionuclide, but chemotherapy conducts leveraging the Samata statin receptor. But I think it's just it's pretty early days. And in terms of the high grade disease, I think one challenges those patients are often more heavily pre treated in terms of chemotherapy. So my list depression is going to be an issue. The other thing is it takes six months to get pr tion. So um you know, in a lot of the kinetics of these tumors when they have a K 67 95% you know, can be very difficult. So in that one paper I showed you with with poorly differentiated neuroendocrine with a high K 67 The median time, the progression was under six months. So you're barely like you can barely get a couple of doses in and people are progressing. So I think it's lots of challenges there. But but stay tuned. Wonderful. Thank you so much for that. Excellent talk. And I think it's really fascinating for the audience. These the talks will be posted and uh you know, people were interested while you were talking Emily and potentially having copies of the slides so we can deal with that later if you want to have slides by pdf available to our audience. So we're going to move on and talk about pancreatic cancer with Margaret tempo and we'll have time for Q and A after that talk as well. Thank you. Hope can you see my slides All right, we're going to move to the execution pancreas. I want to start by just reminding everybody that we're pretty much winning the war on cancer in the major most common cancers. We're seeing really dramatic declines in mortality, sometimes declines in incidents as well. But sadly in pancreatic cancer, I'm trying to find the little arrow here. We're seeing a really steep rise in the incidence and it's on its way to becoming the most common cause of cancer related death. So this is a really scary statistic. One of the reasons has to do with successful aging. The more you successfully age and you don't have other competing causes of death. You're more likely to get cancer, especially pancreatic cancer. And as you can see here, the incidents goes up with every half decade. Now, this is a really tough disease. It's one of the most refractory of all malignancies and you know, we don't know all of the reasons, but we do know that most of the patients are diagnosed with advanced and respectable disease because there really isn't much in the way of early signs And of those who are able to have resection and subsequent adjuvant therapy 50-80% will relapse. And the reason that range is so high is that it kind of depends on what therapy you're able to apply after surgery. Many patients are not candidates for adjuvant therapy following surgery because of ongoing uh complications related to the surgery. So the cure rate is only 10% and the median survival of patients with metastases without treatment Is only about three months. So I've already mentioned that there are no early symptoms. We think that in the majority whips and the majority of patients there's very early invasion and metastases. We think that this is relatively chemo resistant and that meant that the the cancer cells may be existing in sort of a sanctuary of desmond play asia the reaction that occurs around the tumor. And we also know that these patients are very sick at presentations. So they have a lot of debilitating cytokine mediated symptoms that make it difficult to use the treatments that we might so easily give in other malignancies such as breast or colon cancer. We know how this cancer develops. There are basically two routes. One is a dis plastic route where the tumor evolves with inducts that have increasing dysplasia which we call pancreatic inter epithelial hyperplasia. And we also know that there's sort of an adenoma adenoma carcinoma sequence with I. P. Mn introductory popular music. Miss niya plasm and muse narcissistic neo plasm in the end though the disease looks the same so you can't tell when you get a biopsy what the what the precursor lesion was likely to be when I teach medical students about the biology of this disease. I always show the slide and basically this slide gives you the characteristics. It's hard. It's got the highest atomic force measurements. It's hypoxic, the lowest oxygen tension of all malignancies. It's hypo vascular, very little of this in this slide represent nests of adenocarcinoma cells. It's predominantly desmond play asia and it's also hyper vascular, you can't see vessels in there. They may be there and they may be they may be squished by the decimal place to Emily showed her arrow. I wish ours had as much on it as hers does. And if you looked at the therapeutic arrow for lung cancer would be very very cluttered. So we don't have a lot of tools to work with. We have our main horses are workhorses are full fairy knocks and Jeb side of being an and paclitaxel at presentation. We can use like chicken and five F. You in uh in patients who were previously treated with jump side of being an and paclitaxel and and we have um the liberty when we can find patients with with either as a high tumors, high high tumor mutation burden or interact fusions or our our patients with B. R. C. A. Or pal B. Two mutations. We do have targeted therapies that we can employ now fulfilling X. Got on the map because of this particular trial. And it's important to note that this trial was done in a region of France where they had very good backup support good biliary care. They had access to growth factor. Um These patients got class a treatment. There was a typical randomized trial very simple where patients were randomized warfarin ax or genocidal bean. They had to have a very high performance status zero or one. And of course they were followed every every two months with imaging. This is the overall survival and this was the first time we had ever seen a hazard ratio of this. Of this magnitude in pancreatic cancer. And I was I remember giving the discussion at asco and saying that I felt that it was a watershed moment and that really the next step was to get this into the adjuvant setting so that we could cure more patients. But that said this is a tough regimen with dominating toxicities. A mile of suppression, diarrhea and neuropathy. And basically we do have to modify the modify this in order to make it tolerable. We almost all of us admit bolas five F. U. We are happy to reduce doses when neuropathy from oxalate platon starts to starts to escalate. Where were quick to eliminate our sally platon and we also use chemotherapy holidays to give patients a break. Our other regimen jumps out of being an impact attacks all got on the map because of this particular trial. And this trial was different in the sense that it was a global trial. It was conducted in many countries that did not have the some access to some of the the supportive care that one would like to see. So there were a lot of lot of eastern european uh countries that were involved in the conduct of the study. And this also included patients who had a lower performance status. So it may not be surprising that the hazard ratio was not as great, but it was still clinically meaningful at 0.72 and it's certainly quickly got onto the NCC and guidelines based on this study that said this is also it's not as hard as felt very knocks but it is still not a walk in the park and we usually by um I would say by the third cycle for sure we're starting to adjust the schedule and my habit is to alternate the schedule with every other week with a fixed dose rate jumps side of being. Um And sometimes I start patients on that because some we have some patients who aren't quite up to, I think up to getting the three weeks out of four and I I really anecdotally don't think that there's much much effect on efficacy by doing that. So it's a chemotherapy holiday safe because I advocate for that and a lot of cases. And I use this trial to support that this trial was actually done not to test that concept. It was done to try to figure out if we could do something about the neuropathy with warfarin ax. So in our may they got 12 cycles of Clarinex and then we'll put on maintenance in R. And B. They had eight cycles of full fairy knocks and can then continued on with five F. U. And locavore. And then R. C. Was a sequential treatment with a jump side of him. The important thing to note is over on the overall survival slide that there wasn't any difference if you continued treatment to progression versus giving a chemotherapy holiday. And so that that really in my mind supports the idea of giving people a break And I must say patients just love it. Just being able to sort of be have you know reclaimed their life and take trips and do what we all like to do when we're not troubled with covid. So maintenance of response. Is that a new window of opportunity? Well I think so I advised astrazeneca on the design of this trial which was to take patients who had not progressed on who had Bracha mutations or Poppy two and had not progressed on a platinum containing regimen to randomize them to elaborate versus placebo. The endpoint was progression free survival and it certainly meant that pre specified met the pre specified endpoint. It didn't meet the overall any overalls didn't show any overall survival benefit I should say. And it wasn't really powered to do that. It would have taken them 10 years to enroll in this trial had they tried to accomplish that. And I defended this trial to Odak with the FDA in the in the sense that I felt that there was this tail on the curve where patients really seemed to get additional benefit and really prolonged um remission with the addition of elaborate. So you know the life cycle of a cancer therapy. We started out in metastatic disease. We gradually applied the treatments to less extensive disease in the hopes of getting more cures. Well our our effort in the antarctic therapy of pancreatic cancer. If you look at you know, until recently we weren't moving the bar very much until a trial was done by aspect for evaluating jump side to being a cape side of being versus versus jump side of being alone. But then we had the prodigy group coming in again with a really beautiful adjuvant trial of modified full fare Knox versus jim side a bean. And these were very highly selected patients. They they basically were able to get resected obviously They had a postoperative CT Scan which was able to rule out very early recurrence. And we see this in about 10% of patients And they had patients with c. n. 99 levels of less than 180. So very highly selected. It probably isn't quite like the real world, but nonetheless it was an excellent study. And again the hazard ratio was really profound here. Now we're looking at a You know at five year survival that is really approaching 40%. So um you know, I really felt like this um this trial has has made a huge difference for for our ability to get more patients to cure. I'm sorry I was just showing a progression free survival. This is the overall survival. My my gallery is in the way of my slides and I don't know how to change that. So maybe if I just minimize it, Sorry, I'm still new at this, you guys. So we thought then that jump side to being plus um nam paclitaxel um you know, ought to do something similar. Maybe not have this profound effect perhaps, but we designed this trial identical to the full fairing Knox trial. It was a global trials. It was conducted not just in France but all over the world. I had the fortune of our misfortune, I should say of leaving this trial. We had a primary endpoint of independently assessed disease free survival and we didn't meet that endpoint. We didn't even come close. However, investigator assessed disease free survival was a little bit better And it struck us in retrospect that uh you know, when we're seeing patients in the clinic and they're getting more pain and we're seeing changes on CT Scan and they're seeing 99 is going up. We're it's pretty easy for us to call progression. But for radiologists who were independently looking at films without any clinical information, it it just doesn't work as well. Our overall survival for the intention to treat population also didn't prove to be clinically meaningful. And I find this very curious. I have no explanation for it, except for the fact that maybe in micro metastatic disease, this the nab paclitaxel doesn't work as well. And maybe somehow it acts as a depot in bulkier disease. That's the only explanation I can come up with. So that said, what about Neo adjuvant therapy? Uh you know, the patients, about 25% of patients can, as I mentioned, can't get post operative therapy. What if we switch the sequence? Can we get more people to an R0 resection? Well, it turns out we can, and this allows for reception about 20% of patients with locally advanced disease, which, you know, frankly was unheard of just a few years ago, we don't it's not a panacea. We're not entirely sure that even though we get them to resection that we're curing everybody and we really do need a biomarker for chemo resistance because this is a really big deal. Um we can't always tell whether we're helping someone if they don't have an elevated c a 99 for instance, we usually don't see shrinkage at the primary site even when we're actually sterilizing the tumor. So we actually need to know whether um whether our our our treatment is uh is likely to work. There has been a randomized phase two trial of both fulfilling knocks and jump side of being in a vaccine. It was a cooperative group trial and it was in clearly respectable pancreatic adenocarcinoma. Basically patients received um a few cycles of each regimen before surgery and then some after surgery. and basically the rate of R0 resection was the same and the overall survival was the same. So while jump side of being an impact of textile doesn't seem to be as effective given post operatively it clearly has a pre operative role similar to um modified full fairy knocks. And so I think we're very comfortable with um with using using that treatment in the Neo adjuvant setting. There's been some recent additions to the NCC N guidelines and I'll just run through that really quickly. One is that we do recommend germline testing for any patients with pancreatic cancer. Just as Emily mentioned, so many of the neuron underground patients have germline mutations. We find that 8 to 10% of the patients with pancreatic cancer have have a germline mutation. And you know, this is really useful sometimes for the patient but also definitely for the family because with some of the syndromes, you can clearly tailor screening programs that will help diagnose disease early. We also recommend molecular analysis of tumors in patients with metastatic disease. And the reason I think that we're willing to look for the needle in the haystack is that that you know we have so few treatments. And so if we can find that one patient who can get transformative benefits for instance with an M. S. I. Too high tumor and embolism um we're willing to look for it now. Um I talked about treatment implications with with patients who have a BRAC or pal bt mutation. Um One of the things we've learned recently is the robust effectiveness of jumps item and insist platinum in this patient population. And this trial was a trial that was done with apart inhibitor that actually wasn't very good. It was a trial run by Eileen O'Reilly and they were trying to look at the addition of the lab ready to jump side of being insist platon. But it was this trial that actually got jumped out of an insist Platen on the N. C. C. N. Guidelines for therapy for patients who had a break of one or two or possibly two mutations. And the reason it did is that the majority of patients had responses and really deep responses and durable responses and the overall survival in both of these arms with the same chemotherapy background was very impressive. So if you can avoid giving toxic fulfilling knocks and give simple jump site of being insist platinum to these patients, I think you're doing them a big favor. So when we're suspicious of a bracket mutation, we do get a rapid turnaround on the DNA damage repair genes um with the vendor that we use, We can usually get the results in about 10 days. This is just a reminder about the mutation allow landscape in um in pancreatic cancer. This was from a very nice paper done by one of our colleagues here eric collison. And what is important to notice here is that there's about 10% of patients who are ar rass negative. They are truly rast wild type and those are the patients that tend to be enriched with targeted mutations. So that's another reason why I think, you know, doing the molecular profiling on these tumors is so important to find any other possible options for them. Just as a as a case study here that we are following a young man with lynch syndrome who had a prior history of colorectal cancer and presented with locally advanced pancreatic cancer. In May of 2015, he responded really well to the full fairy knocks but then progressed in april 2000 and 16, He began treatment with pem bro in May of 2016 and he responded And this is what happened with the CAIA 99. Just a dramatic plummet it normalized and he has durable control. Um as of today. So I think when when you have something that can be so transformative, it's definitely worth looking. So we routinely get um M. S. Uh M. S. I. Status on every biopsy at UCSF so we don't have to wait for it so that we can think about it and you know have that knowledge ready when we need it. I also think that we have a pretty exciting future ahead in terms of rest targeting rests um point mutations. This was a presentation that was given at the Oscar G. I'm meeting in january, it's with the progressive molecule, it's moratti's molecule. And basically they had it was in G. I. Patients and they had only a few patients with metastatic pancreatic cancer. Now this drug targets only G. 12 C. Which is only about you know, a few percent of our patients with pancreatic cancer. But the responses were really good. Again, majority of patients having a response and some being very very durable. And uh cavon Shaukat at UCSF who basically developed this drug really believes that they should be able to address all of the common point mutations. And so I think we're going to have a new class of targeted therapies available for our patients in the near future with that. I thank you very much for your attention and I'd be happy to take questions. Thanks so much. That was great turning on my video here. Really great and so interesting to see how far pancreatic cancer has come. We tend to be all in our own silos here. And somebody asked a question which actually came up to me also. So, you know, we found in triple negative breast cancer, which I would certainly say is closer to pancreatic cancer than some other types of breast cancer. Um That if you give a chemotherapy holiday that survival actually was decreased. And that was seen in two different studies, both with more modern day treatment in the past. So the question is, why does it work here? And Mary Petrovsky asks for the chemotherapy holiday consideration. It looked like there was a difference in survival of 18 months, although not at six and 12 months. And she says maybe she just missed the p value for significance on that slide. Well, you know that trial wasn't powered to show a difference in overall survival. They were really looking at chemotherapy induced neuropathy. So, um so we're only inferring that that the that it's safe to do a chemotherapy holiday. But I will say that in europe they routinely do a chemotherapy holiday. It's never been popular in the United States for whatever reason, but in europe it's very routine. And their statistics seem to be very good. I mean, there survival's and some of the studies that are done in, you know, just only in europe or in France, for example, with the Prodi's group. Um everything that's that they're there, they've been teaching us. So I'm I'm very comfortable with chemotherapy holiday and I get a scan every every eight weeks. Do you wait? So you patient has a good response? Right. Do they have to have a Cr or pr and then you scan them every eight weeks? And do you only restart when they start having evidence of progression? Right. But they don't have to even have a really good response. Because sometimes if I have a patient with stable disease who's exhausted with their chemotherapy I'll give them a break so that they can tolerate the next because you know they're going to progress soon and if they have a break they're more likely to be able to tolerate you know appropriate dozing with jumps out of being a net back backward hassle. That's really interesting. And then and of course the neuropathy is a big issue. We've been looking although we're not looking in any kind of study way just simply because it's a funding issue so far. But a lot of people are using these cold gloves and booties which I've now recommended to everybody getting neo adjuvant or adjuvant weekly paclitaxel for 12 weeks because you figure it's such a little thing to do relatively cheap. And if you could not have uh if you could not have neuropathy that would then make you miserable for the next five years. That would be really good. Now obviously for medicine clinic pancreatic cancer. It's not as much of an issue but still have you used those you know we were actually working with the infusion center to implement this? There's we we belong to a quality improvement network called canopy. And I learned that one of the meetings that Seattle is routinely using, um they're not they're not doing the gloves, they're basically just doing ice baths four ft and hands and they're using it both rock sally and they claim success with that as well as the tax savings. So there was some study at Mayo clinic with Charles liu princes group where they did not find a benefit with tax scenes with ice bags. Um and there is also a dimensional data from Singapore suggesting you need to have very sort of close opposition of the cool to your hands rather than just making them cold overall. Anyway. It's a fascinating idea. Maybe it would help with tolerance. Another question is, you know, we're all about cell free DNA now. It's already exciting. You know, work and then we help help us with mutations. And for pancreatic cancer, it might be hard to get a biopsy depending on where the tumor is at least risky for the patient or painful. Do you use cell free DNA? We do when we don't when we can't get sufficient tissue from the biopsy specimen. But I must say that we often come up empty on that as well. So I think a lot of circulating, not as much shed really interesting. Um and then is there, you know, you mentioned the mutations uh and screening for mutations which I think is really fascinating in a kind of a newish area right. Um Is there a screening that should be done for pancreatic cancer in people with family histories? What what do you tell people who are worried? I mean pancreatic cancer is one of those terrible cancers that you only diagnosed when you have terrible disease. So we we can't screen like a mammogram. Well right now for for families certain syndromes where you have an eight fold or higher risk because of the mutation. We do recommend screening with either U. S. Or M. R. I. We tend to use M. R. I hear M. R. M. R. C. P. Sorry M. R. C. P. Because we have limited capacity in our advanced endoscopy units and it's just easier to do the M. R. C. P. But there are pancreas cancer families where a single mutation does not explain the family. And so those those families, when we identify them all uh family members are Recommended to have screening at starting at 10 years earlier than the youngest affected person. So similar to what we do with Bracha mutations actually. Yeah and we don't um for instance if a Bracha family has has no evidence of pancreatic cancer. We aren't recommending screening for pancreatic cancer in those families whether we're right about that or not. I don't know. But the risk ratio is really pretty low with both Braca one and record too. Although we certainly see them. That's really interesting. Well made a lot of progress in pancreatic cancer now and uh hopefully earlier diagnosis will help. But there isn't really anything else for early diagnosis, right? Because we don't really know who's at risk. That's correct. I mean we belong to a new onset diabetes is an early sign of the disease. We don't know if that's early enough but we I'm working with the N. I. D. D. K. And a large cohort working with Kaiser. And so we're trying to see if we can use that group. We have we are joining a consortium called proceed which is based at N. Y. U. And this is for patients with hereditary predisposition. So hopefully we'll start to learn a little bit more and figure out what we can do and test the available biomarkers. But you're right. The biggest problem is identifying the cohort that should be screened because there are a lot of biomarkers out there that are potentially useful. Yeah, I think that's one area where we really need more advanced. But um it's definitely the field continues to move forward which is really exciting to hear. And it's great to hear from you such an expert in this field over the time course when pancreatic cancer really had no treatment options until now. So pretty amazing. Thank you very much for participating and to the audience. Of course these talks will also be posted on the cancer center website which is in your chat. Um so now we're going to move on and talk about sarcomas and surgical management of sarcomas. We're really excited to have. Roseanna was struck in here, who I introduced to you earlier and she will talk about the surgical manager of sarcomas, but all questions are available for you. So, if you want to ask questions about some surgical management of cancer, metastatic to bone, this is a great place to ask it. Thank you so much for inviting me to speak today. Um so my goal is to just talk a little bit about how surgery fits into the multidisciplinary management of sarcomas. Um I want to show you guys some of the different reconstruction options we do for bone and soft tissue sarcoma receptions and then I want to be transparent about some of the complications in the sea. Um I know you all know this but I like to show this to all of our learners um just to let everyone know how diverse sarcoma is really are. So the malignant plasma as you know, and we can see sarcomas um with smooth muscle, smooth muscle markers and we can see those, you know, you often think about um like Romeo sarcoma or uterine lymphoma sarcoma but we see that in the bone and we see that in the soft tissue as well. Rhabdomyolysis are comas. We see ups all over the trunk, the thighs most commonly. We also see a lot of different bone sarcomas. Um Condra sarcoma have looking a lot like regular cartilage, osteosarcoma, obviously a lot of life. Oh, sarcoma. So we see a very um large variety of different types of tumors. This is a slide I actually got from dr harvey in one of our bone and soft tissue pathologists here. And what he did is he looked at um published papers that characterized the number of sarcoma, is that had genetic or molecular aberrations. And he looked back from 1970 80 94,010. And you can see there's almost an exponential growth of descriptions of novel genetic or molecular abnormalities within sarcomas. And so if you look back at earlier versions of the bone and soft tissue Um pathology textbook, there were maybe 50 different distinct types of Sarcomas. Now that is well over 200 distinct types of sarcomas. So it's a very heterogeneous heterogeneous group of malignancies with a very different type of treatment and outcomes. I treat patients all the way from, you know, two years of age is the youngest patient I've treated surgically for Sarcoma all the way up to 98 as the oldest patient I've surgically treated with the Sarcoma. So we see patients all over the age spectrum. What these graphs are demonstrating is that primary sarcoma of the bone are a little bit more common in young people and that's driven primarily by osteosarcoma. Osteosarcoma is the most common primary bone And it is common in adolescents. So the peak age for us to Sarcoma is about 16 and that's why the distribution graph is skewed a little bit to younger individuals. Um for bone, the reverse is true for soft tissue sarcomas. So I'd say the most common age group we see for patients presenting with a large soft tissue Sarcoma is probably 50s and 60s. Um soft tissue sarcomas are about 10 times more common than bone sarcoma. So a lot of people think of me as a bone doctor but actually I probably do equal if not more soft tissue sections. And that's because soft tissue sarcomas are more common than bone sarcomas. I do a lot of the bony work though with metastatic bone disease. And and one thing I'll say to dr tim pero you guys are doing a great job because we are now starting to have patients present with metastatic pancreatic cancer to the bone and impending or pathologic fractures, which we never used to see because patients just weren't living long enough to develop boning next. So keep up the good work and and we'll do our part. So if we look at adult soft tissue sarcomas and bone tumors. Bone sarcomas again all over the body. The most common location for soft tissue sarcomas are in the side. The second most common would be the retro peritoneum in the trunk. For bone. Again, it's the femur most common location for primary bone tumors, pelvis and the humerus. But we're really talking about all the way from the shoulder to the ankle. Um We do see osteosarcoma is in the job but that's not something I treat. Although the head and neck surgeons do see a lot of that. So I really want to emphasize how I am just one piece of the team and that sarcoma is being so diverse and so rare. It's really important that they're treated at a cancer center and with a um an experienced multidisciplinary group. So the N. C. C. N. Actually recommends that prior to any therapy for sarcomas whether that's chemo therapy, systemic therapy, radiation therapy and or surgery that patients shouldn't be seen by a multidisciplinary team, expertise in sarcoma. And I feel really lucky that we have an excellent team here and I will I will stand by this statement that I think we have the best weekly tumor board. Um We have about 20 different um clinicians joining our weekly tumor board sarcoma tumor board. Um We now have three excellent medical oncologists with the addition of brian Sheltie. Um He's also opening up new clinical trials for systemic treatment for sarcoma patients. Which is wonderful. We have a really large pediatric oncology group. I've just listed um three here that do a lot of the osteosarcoma and ewing's sarcoma work. So Alejandro speak cordero. Um It's sadness and rob Goldsby. Our bonus soft tissue pathologists are excellent. Andrew harvey and new york or Bonnie who's been here for a couple of years now. And Susan Co radiation team, we have Alex dot chuck and steve Brownstein are on the weekly tumor board. Our musculoskeletal radiologists are really an integral part of our team. They perform a lot of the biopsies for us. It's a one of the things that's changed with sarcoma diagnosis over the past 10 to 15 years is we're moving away from open surgical biopsies for tumors and relying heavily on our musculoskeletal radiologists. They do a lot of ultrasound guided biopsies and that's done every friday at the P. C. M. B. As well as ct guided biopsies that they'll do for any bony tumors. Michael Mann is one of our thoracic oncologist that does many of our medicine detect amis with very good results for patients with although metastatic disease and we work really closely with our surgical oncology colleagues. Um And oftentimes will operate together for large tumors in the pelvis. And then my group Richard O'Donnell has been here for a little over 20 years. He's the overall director of the sarcoma program myself. I'm the chief of our division as well as our newest partner dr Zimmel. Um and all of us are full time worth pentagon colleges. So I just wanted to show you a couple of cases to illustrate some of the thinking that goes into the surgical treatment of these patients. So this was a patient, eight year old girl very, very active was scooting, fell off her scooter and had a lot of pain, more pain than you would expect from a simple fall. Parents took her to the emergency department slash urgent care where they got these X rays. And when you look at these X rays you can your eyes immediately drawn to the distal femur where it just looks, one might say a little bit moth eaten that looks to be permitted changes. And then on the lateral view you can actually see the fracture line right here. You can also see some evidence of new bone formation. So she unfortunately was diagnosed with an osteosarcoma. Um and you know, again surgery is part of the treatment but it is not the treatment. So, I really like to reflect on this that in the pre chemotherapy area era where the really the only tool was an aggressive surgery. So in the 1960s or 70s a patient like this will be treated with almost limitation doses of radiation to the distal femur. And then it hit this articulation. So you can't get much more radical than that yet. There was only a 20% 5 year survival. And so the conclusion was that for us to Sarcoma, of these patients had metastatic disease and presentation now fast forward to the modern chemo era. And we we are seeing 65 to 75% 5 year survival rates. Um and it allows us to do more limb sparing surgery. And so surgery is part of the treatment. But the real changes come with advances in chemotherapy. However, a lot a lot has become stagnant over the past 2030 years. This is a graph looking at the 10-year survival rate by decade. So you can see in the 1960s Um it was estimated 10% 10 year overall survival 1970s With the advent of chemotherapy jumped to close to 50 19 eighties. The treatment switched from mono therapy to multi agent chemotherapy. And since the eighties there's been several different um studies, multi institutional studies through the Children's oncology group, looking at different combinations of chemotherapy agents and does sings But really not. A lot has changed in the 10 year survival for these patients. So an area where more research needs to be done. But anyway for these patients now we tend to treat them with the chemo sandwich. So, new adjuvant chemotherapy local control which consists of a wide resection surgery and adjuvant chemotherapy. And when we meet with these patients, we really have to center the discussion and let patients know and their families specifically that our number one goal is to contribute to a cure that we believe that with good chemotherapy and a good surgery, we can achieve a cure for these patients. And so that is the number one priority. And it may come at the cost of a limb as much as we don't like to do that. But life is more important than the limb. So if we can achieve limb salvage, then we want to achieve the best function for patients. Lower down on the priority scale is limb length equalization and cosmetic parents. Okay, So I mentioned earlier that once chemotherapy became the standard of care, we began to do more limb salvage. So this is a landmark study from 1986 and it showed the overall survival progression free survival between patients that had a limb salvage surgery with the solid line and above the knee amputation with the dotted line and a hip disarticulation. And you can see there was no statistical difference between these three groups. And so now with chemotherapy, better imaging modalities and better modular implants, limb salvage is appropriate in 90% of patients that present with an extremity, um Osteosarcoma or any sarcoma for that. Alright, so back to this patient. So now we've got to think what can we do for this patient, This eight year old girl who's very, very active and wants to be as active as possible but also wants to have a normal leg. Um So the one thing that we have to think about is what are we going to do with her growth plates. So the majority of growth and a child comes from this distal femur growth plate because the tumor is here, we know that we will be if we want to get our wide reception. If this is our tur a wide resection is really going to require negative margins and we're going to have to include that growth plate. And so this makes it difficult to think about. What type of surgery can we offer. Well, we could offer an above the knee amputation. We could offer a rotation plastic which is gaining popularity but in short is where you would remove the distal femur, you remove the proximal tibia, you remove both of those and throw it throw it away and then you bring up the ankle and the foot and you replace the knee with the ankle and the foot turned around backwards. So that is an excellent surgery. But not something that an eight year this particular eight year old girl wanted. We can do donor bone, we can do a metal implant that allows for growth or bone transport. She chose a metal implant that allows for bone growth. So this is about a year after surgery. So you can see that we remove the distal femur here. He gave her a new total knee replacement. And right here is a telescoping mechanism that allows us to lengthen this implant over time. And this is her seven years later and you can see that she has grown her growth plates have closed and we lengthened her in total about seven cm. And then this is her playing golf for her high school team. So this is a great example of how new technologies allow us to keep patients functional without sacrificing um a good oncological surgery but there are complications. And so you know, unique to end a prosthetic or metallic Implants are unplanned revisions or failures. So our study from 2015 showed that at 10 years half of our patients had an unplanned revision. And the way I explain it to patients is let's say you take a paperclip and you move the paper flip, flip back and forth, back and forth. Ultimately it's going to break because it's only metal and that's what we see with these huge metal implants. They are susceptible to fatigue failure. So we're constantly trying to improve the technology. So they are more durable. The second huge complication is an infection. This is a Kaplan Meier infection free survival curve from this large global prospective randomized trial run out of McMaster's. We were a participating institution. And what they did is they randomized patients to get 24 hours of peri operative antibiotics versus five days of peri operative antibiotics um undergoing lower extremity prosthetic reconstruction for a primary malignant bone tumor. And they found that the infection rate was 16% at one year. And there was no difference in um infection rate based on duration antibiotics and that is a really sobering number. So just to put it in context if any of, you know someone that had a hip or knee replacement, the risk of infection following a primary total hip or primary total meat is about 1% or less. So this is an order of magnitude higher. And part of it is because it's so much metal. Part of it is because a lot of patients are immuno compromised from chemotherapy and part of it is from all of the soft tissue damage from the surgery itself and the length of the surgery. So infection is a big problem that we're trying to solve. And unfortunately, up to a third of patients that have an implant infection ultimately go on to an amputation. All right. So here's another case that is a little bit interesting. So this is a 26 year old woman, right hand dominant and she had this long standing um lesion in her ulna that was thought to be a benign bone tumor called fibrous dysplasia, but slowly worsened over the years and was inappropriately treated with what's called a curettage. So, scraping out the tumor packing with coral chips and a metal rod. After this surgery, when the pathology was reviewed, it was found to be an adamant in number. So nana Manteno was incredibly rare and it's it's it's a low grade malignant sarcoma basically there is metastatic potential, but a really high five and 10 year survival rate is not generally treated with chemotherapy or radiation. So what do we do for this patient? It's a contaminated field, you can even see the coral chips and soft tissue. We don't have any adjustment options to clean up the contaminated field like radiation, it's her dominant arm. But on the other hand it's a low grade malignancy and she has no evidence of metastatic disease. So we could do a lot of elbow amputation which is functionally pretty devastating when it's your dominant arm. We could take the entire arm it and leave her with just the radius and a hand. But that's a very unstable elbow or we could get creative. So she opted for us to get creative. So what we did for her is we broke her surgery into two stages trying to keep it as safe as possible for margins. So stage one was removal of the pen and a wide resection of the ulnar shaft as well as distal following that. We waited for margins which were negative and we got a new M. R. I. Scan. Once we were satisfied we convert converted her to what's called a one bone forearm. And we left her in slight pro nation. So it makes typing a little bit easier. But she's sort of stuck in this position and in order to move the hand in space she really has to move at the shoulder and she can move the elbow And she's done well she's about 18 months out. She's back to work at whole foods in the Bakery Department. And she has great hand function. So this was a a good example of getting creative trying to keep principles of negative margins surgery as well as functional maximizing their function. And I did this surgery with my colleague who is an elbow specialist. So we used his expertise with elbow reconstruction and my expertise with tumor resection. Okay, finally, a little bit more bread and butter. So this is a 71 year old gentleman with a left thigh, mixed Lloyd Lipo Sarcoma. So unfortunately he had had about a year of this mask, but it was thought to be a hematoma. Ultimately it wasn't behaving as a hematoma and a biopsy was done which showed a mix. So I'd like to start drama. And the challenging part here is this red arrow shows us the superficial femoral artery completely encased with too much. Okay, um so this next word, life of sarcoma basically. Um what we know is that the prognosis is really based on the percent round cell component. Because we can see round cells as well as spindle cells and these immature lipo blasts, he had very low round cell component. And we also know that they are very sensitive to radiation. So after discussing, you know pros and cons of surgery, we decided that he would benefit most from the radiation. He received 50 gray of radiation and had a dramatic shrinkage of the tumor. So, pre radiation to post radiation, but unfortunately that vessel is still encased. So again, a great example of why I love UCSF is it's very easy to collaborate. Um So we decided to proceed with wide resection. This Rainbow line shows are planned resection including the vessels. Um We had the vascular surgery team come in and do a vascular bypass with being autographed from the contra lateral leg. And then due to the irradiated field as well as the bypass. We had the plastic surgery team come in and do a rotational muscle flat. And so this was a good example of teamwork. The yellow arrow here is showing the cyanotic. So complications from you know our standard treatment for soft tissue sarcomas which include radiation and wide resection. A lot of these patients have a persistent hematoma or Ciroma. This particular patient has had multiple um Ir guided drains place because he'll get a symptomatic Ciroma as a result he's had some static nerve irritation but no weakness almost. Um Not all but a very high number of our patients get link lymphedema following a surgery radiation. Fibrosis can be a late effect. Um They are more susceptible to infections or wound healing complications. And long term patients that undergo reception of a very large mass that includes stripping of the bone combined with radiation are at risk of late radiation. Just fractures and these fractures almost never heal. Um And then just one slide on some new technologies. I hope this isn't too graphic. But this was a patient of mine that had a recurrent Condra sarcoma. So this is the T. two axle Emory and what you're seeing here is a cross sectional view of his pelvis about the level of the hip joint and here's his bladder, here's his rectum. And then all this white stuff is the Congress are calmer. Well I was having a hard time orienting this in my head and coming up with a surgical plan. And so here in the at the Mission Bay campus we actually have this amazing three D. Printing lab. You can put your request in online and they make these beautiful models. So with this three D. Model I was much um it was much easier to visualize exactly how we wanted to do the surgery. And so with this model we were able to plan a hemi Saqr ectomy. So we came down the middle of the sacrum we took the lateral aspect of the L. Four and L. Five spinal processes and transfers process. And we actually did an external homies holla back to me and came through the paris and facil region like this. And this is the tumor specimen on the back table. And then this is um let me clear all my drawings and then this is showing him after this where he has spinal hardware fixated to the right heavy pelvis and we've successfully removed too much. So in conclusion surgery is just one part of a multi disciplinary approach to sarcoma treatment which I think is the only way to treat sarcoma as um I don't think it can be done alone or an asylum that has to be part of a larger effort. Um Are negative margins are always the goal with our surgery, but we are trying to maximize function as much as we can. Um and teamwork utilizing everything that our institution has to offer um gives patients the best oncological outcomes. So thank you. That was amazing. I think that three D. Printing was just so cool. It's incredible. It's amazing that you can plan that. I imagine sometimes you still end up with something you didn't quite expect no matter how well you image anything. And it's also amazing that you can survive without half of your pelvis. You know, that's also pretty incredible. Um Obviously, you know, the longer people lived and were complications we see from, you know radiation and uh we tend I have to say in breast cancer now where women are living longer. Sometimes we get these compression fractures or fractures that create all sorts of problems when they have lived a long time. But you know, people with sarcoma who are cured live a really long time. So then it's hard to know how much radiation and how you're should do it. And so are there ways to try and minimize that toxicity? Yeah, that's a great question. Um So you know, for a large um high grade soft tissue sarcoma patients can either get about 50 gray of neo adjuvant radiation or 65 gray adjuvant radiation and it's kind of you know pick your poison. So we know that if you do the radiation before surgery there's a much higher wound healing complication rate. If you do the radiation after surgery lower wound complications but then higher rate of radiation fibrosis, lymphedema fractures. Um So my practice has actually shifted to neo adjuvant radiation because with I. M. R. T. The fields are getting tighter and there's less toxicity too the bone and less toxicity to the muscle. And you're kind of respecting some of the muscle as your margin that's been damaged by the radiation. So trying to shift to more new adamant radiation and more of the I. M. R. T. With tighter tighter fields as well as some people not at our institution use proton beam. That can also even be more precise. That's great. That's really great to hear because you know we definitely see the problems with wound healing and what and breast cancer. But I think even more so um the larger fields that used to be used are so problematic and lymphedema is a horrible complication particularly the leg where you know we just like like really why are you getting that breast cancer? It all has to do with giving chemo that propensity I don't know the radiation they got to their pelvis. So hopefully we'll see less of it. But you know for sarcoma which is a you know such an interesting cancer of the soft tissue sarcomas are um hard to diagnose and people miss them I think. Are there symptoms that should make us think more about somebody having a soft tissue sarcoma? Is there any genetic component? That's a great question. Um I think that the ones that end up getting missed the most are sort of the smaller superficial soft tissue sarcomas that you think are probably always just a light coma. Um And we see a lot of those come our way where it was taken out by you know their G. P. Or plastic surgeon or you know just oh it's just a little superficial mass and we'll take it off. Um But I think anything that's firm deep getting larger you know that's very concerning. Um And unfortunately sarcoma is tend to be painless. Bone sar comas are painful. Just like metastatic disease to the bone meal. The bone is sensitive when there's something growing in the bone destroying bone. It's painful. But soft tissue sarcomas are largely silent and so they that's why the thighs can get so large before they're recognized. But I will say that the most common um misdiagnosed large sarcoma is thinking as a hematoma but for someone to have a hematoma they have to have a reason to believe they have to have had trauma or beyond crazy anti coagulation and if they don't have trauma and they don't have anti coagulation on board, then you just have to biopsy it. And even if it's a hematoma biopsy, it's never, never the wrong thing. Right? So imaging and biopsy is important. And then just our last question before we closed for the evening is um do you see much secondary cancers and the kids who are long term survivors of sarcoma? Yeah, we do. So I think there they're recognizing that maybe more of these Children, especially ones that are very young when they're getting their first diagnoses may have left Romania or other um you know, genetic abnormalities and those patients we are seeing, I myself have a you know, kind of a handful of patients that have radiation induced sarcomas. So radiation for rhabdo is a pretty classic scenario or radiation for Ewing's. And then you see those patients 10, 15 years later and there's a new sarcoma, either bone or soft tissue sarcoma in that radiation field. And then interestingly, I've seen several patients that have Angio Sarcoma following radiation for breast cancer or other, you know. So yeah. So yeah, we do see it and again, it's usually somewhere between 10 and 30 years down the road. Yeah. Well, yeah, it's a rare complication of breast radiation, but definitely a complication. Well with that, I think we're at time and we so appreciate all of our speakers um Emily Margaret Rosanna for speaking on these in such interesting topics where you've really made big inroads and change practice and I think it's also exciting for me, lifelong UCS effort to see all the incredible advances that you, my colleagues are working on and what UCSF has to offer and to our audience, any topics that you're interested in. Send me an email. Hope dot rubio at UCSF dot edu. You really easy to remember. Um and we're happy to talk about any topics you're interested in will be posting the link of course on twitter and other social media as well. If you have no people who would be interested in listening to this um at a time that's more convenient for them and I'll leave the last words to our director, laura Cristina. So thank you all of the speakers. They were great talks and I learned a lot as well and I love the three D modeling I think. But that's because I'm a surgeon. So thank you for audio. It's cool. It's science fiction. Yeah, that was great. Thank you for our audience. And again, um look, look out for some advertisements, emails, twitter for our next series starting next year. Thank you. Everybody have a great evening. Mm hmm.