Here’s an exciting look at recent improvements in our understanding and management of certain malignancies normally associated with a poor prognosis. UCSF specialists explain a resection-improving technique, strategies for delivering drugs into the brain, and other innovations for glioblastoma; an updated perspective on metastatic disease and expanded use of ablative radiotherapy for focal metastases; and advantages to both patients and health care institutions of a robotic approach to radical cystectomy, now offered at UCSF for more than 15 years.
So we have first Nancy and Oprah Heim. Bush, who is a professor, assistant professor in neurology and neuroscience, is and she's going to talk about the current and future strategies for the treatment of glioblastoma. Um, and maybe she'll talk a little bit about the organizational structure here where we started a national organization that actually works on brain tumors and glioblastoma and have some really incredible surgeons and neuro oncologists. Um, and then Steve Bronstein, who I have on speed dial for my patients with breast cancer, is an assistant professor and radiation oncology. And he's going to talk about some of our advances in radiotherapy for the management of metastatic disease, where I think we've made unbelievable advances. Um, since I started in oncology, Um, and then Raj Pruthi is a professor and chair in the Department of Urology here at UCSF. He's going to talk about a very exciting new area robotic surgery in bladder cancer, something that's been worked on for a long time and I think, really is in prime time. So we're excited to hear about that as well. So remember about the Q and A, uh and then, without further ado, we'll go ahead and start there. The other thing is that there is This is being recorded so that there will be the opportunity to even see, um, the information at a future time. So, uh, Nancy, do you want to start? Sure. Let me. Perfect. Perfect. Okay, so, yes, I'm going to talk today about the current and future strategies for treatment of glioblastoma. And I'm part of the division of neuropsychology and the Department of Neurosurgery and Neurology. So glioblastoma is the most common malignant primary brain tumor, 45% of all malignant CNS tumors and 80% of all primary malignant CNS tumors. It's incident is about 3.19 cases per 100,000 person years and in general, the mean age of diagnosis to 64. That being said, we receive many young patients and also patients into their eighties, slightly more common in men than whites and more common in whites than blacks. And then median Overall survival, despite our best efforts, is still approximately 80 to 20 months. So over time, we've made some advances for the treatment of glioblastoma. Um, we in the seventies, we realized that radiation works really well I'm an old but a good drug. Lowenstein started to be used in the late seventies. Um And then in the nineties, the Glee Adele wafer, which is a way for you actually put into a surgical section of cavity was FDA approved during this time. We also developed better imaging CT scans, MRI scans, and really developed our criteria to understand what it means when a tumor is growing. And then, in 2000, Temodar was approved for relapsed in a plastic Ashley Thomas and got accelerated approval for glioblastoma um, in the two thousands and then a vast in orbit. This is a mob was approved for recurrent glioblastoma. And then more recently, I'm going to talk about something called Novo TTF, or opportune tumor treating fields that was approved for both newly diagnosed and recurrent glioblastoma. So we have made some progress, but clearly not enough. And truly, the three tenets of treatment for glioblastoma remain surgery, radiation and chemotherapy. However, it's far more complicated than that. We have a really multidisciplinary approach between our radiologists are surgeons are pathologists are radiation oncologists. I too have Steve Bronson on speed dial, um, as well as our medical oncologists. And so, from the diagnosis, through the treatment to inevitable recurrence and then back again, we have a multidisciplinary approach with a lot of communication between the different groups to kind of find the best treatment for each patient. So in general, we do like to start with surgery. We know that maximal, safer section is the mainstay of our surgical approach to any patient with a glioma, especially glioblastoma, and we incorporate preoperative imaging. Now, intra operative imaging, monitoring, mapping. So awake language mapping. The surgeons actually wake up patients during brain surgery and have them speak. So we can really get the best extent of reception as well as use of investigational agents such as, uh, a lie which marks the tumor, which I will also show you. We know that patients do better when they have a better reception. So this is an older study. You are T. C 26981 And what this shows is that patients who had a complete resection of enhancing disease had improved overall survival compared to patients who had sub total resection or biopsy. Now this was improved with the addition of radiation and T. Mazzola, my but overall, better surgery, better overall survival. And this is why it's so important to get these patients to really experience surgeons. And that's why we really like to get them to UCSF because we know that we have really some of the best in the world. More recently, our group published a paper in JAMA Oncology showing that maximum extent of resection is extraordinarily important for all patients with glioblastoma, and you can look at survival. And based on this, the patients who had the worst prognosis are those who got no Temodar or no chemotherapy. And patients who are older also had worse prognosis. And then you're able to actually stratify out patients after that based on their extensive reception. So they had really good receptions. They were in the best category, the best overall survival and group for also, some molecular characteristics come into this with the idea of mutation. But in general, patients who had good receptions overall do so much better. And so one way that I like to highlight that was really developed at U. C s F was the use of five l. A. L. A. Is five immuno lunatic acid and what it does. Is it? Basically, uh, it's a poor friend. You Can you take it before surgery a few hours before And then when you put a violent blue light onto the brain tumor resection of the tumor cells actually light up so you can use this during your surgery to actually increase the extent of reception and make sure that you're getting as many cells as possible. Um, it is does There are some limitations. It does get taken up by the P A and Corey plexus. You have to be a little bit careful about that. Um, and as well, you can have some photo bleaching over time so you can't do your entire surgery under violet blue light, but I'm not sure the surgeons would want that. Anyway. However, trials at UCSF have led to approval of this by the FDA. Okay, so once we get the tumor out, we have to figure out what it is. Uh, in 2016, the World Health Organization actually reclassified brain tumors, and we used to do just the classic histology what it looked like under the microscope. And now we also incorporate the genetic features both genome and phenotype. So patients with glioblastoma typically primary glioblastoma have i d h wild type. They do not have an i d mutation or they're called a secondary glioblastoma and usually ate your expectations. Um, and this is now really how we characterize g b m. We look for CK mutations, e g f r. Mutations things that make up, uh, molecular alterations. We know that we see in G b M that we don't see in lower grade tumors. So even if the classic histology doesn't look aggressive, if we see these molecular features, we actually re classify them as molecular glioblastoma as and actually in this year in 2021 the World Health Organization is going to have another update that's going to incorporate this again. More molecular alterations leading to different diagnoses. So in general, um, we have lots of patients with glioblastoma. At this point, everybody gets dinner therapy. However, only a few patients respond to this therapy and and most fail and and this is incurable. Inevitably, people recur, and we don't quite understand why, but it's true that we're giving everybody the same thing without really understanding the differences that each patient has with their molecular characterization. And so the gold standard is to really go to a personalized medicine approach where we can figure out what makes these patients different, what makes their glioblastoma different and then be able to really tailor our treatments to them? And that's really the direction that we're going. However, we're not quite there yet. At this point, patients who have glioblastoma all get the same kind of standard of care therapy, which includes both radiation and chemotherapy. So, like Dr Bronson, you'll hear him later. Um, he will take our patients and do stand radiation, which is 60 grade four glioblastoma, delivered in 32 33 fractions. Um, we do the entire tumor field, plus a +123 centimeter margin to treat any of the infiltrating tumor, even if it's the gross total resection. And then in older patients, we do know that we can give them hypo fractionated courses so short courses down 23 weeks that have about the same efficacy. But it and improved side effect profile with the radiation we give daily teams. Olumide Timisoara mine is going at a low dose daily during radiation every single day. They don't get the weekends off like they do with the radiation therapy and then, following the six weeks of radiation therapy, will do achieve intimacy. Olumide higher doses, actually double the dose with a five day on 23 day off cycle will do this at least six months, sometimes up to 12 months, depending on the patient on their blood counts. And Covid has changed a lot of things like that as well. Team is Olumide is an oral side of toxic, DNA calculating agent, and it did improve our overall survival compared to radiation alone to 14.6 months from 12 months. But it did have a twofold increase into your survival from 10% to 26%. And here's the seminal paper that showed that we could have an approval with chemotherapy. Team is Solomon, and so patients who did worse had radiation only and had something called mgmt UNM methylation Patients who did the best had radiation chemotherapy and had something called mgmt methylation. Mgmt is a DNA repair jean. We know that Temodar breaks D N a M GMT when it's active, comes along and fixes the broken d n A. And so Mgmt is in its inactive state when it's methylated. So we know that patients who are methylated have a better response to to meet our. That being said, even patients with a new methylation have a tail. We do see that these patients do have a response. At least 5% of patients do have a response. So at this point, even though we know that those patients don't tend to have a good response to the Temodar, everybody is getting radiation and seminar. So going back to this idea that we really need to find better treatments for each individual patient now a new treatment that many of you may not be as aware of because it's a little bit different than other things and other kinds of cancers is called alternating electric field therapy, or TTF tumor treating fields. And this harness is the idea that you can use alternating electric fields with electrodes on the brain to actually disrupt mitosis. And so the idea of these electric fields actually interfere with the production of spindle fibers. And so when the cells are trying to divide, the spindles don't form and these cells can't undergo normal cell division. So the picture on the right is actually what it looks like. Our patients have to shave their head. They wear four pads of electrodes on their head. Um, and if they wear this continuously at least 18 hours a day through a given team is Olumide. There was a significant overall survival benefit of about four months for patients who wore the TTF with their achievement. Team. Is Olumide now? You might say, Oh my gosh, four months, that's not that much. I just told you that chemotherapy gives us too much more. So it is something. Uh And then also analysis actually showed that patients who wore the TTF it doubled the five year survival rate. So patients with just Temodar alone had a 5% 5 year survival rate. And when they were the TTF, that increased to 13%. So this is a treatment for patients with glioblastoma and newly diagnosed. It's also a treatment for recurrent patients as a sole agent based on a non inferiority trial that was done compared to chemotherapy that the oncologist thought was the correct choice for that patient. Okay, so inevitably, glioblastoma does recur, and at this time there's no really standard treatment for patients with recurrent glioblastoma, and we think about each person being an individual. Does it make sense to do more? Surgery hasn't been two years since the radiation Or is it outside the radiation field, or is it amenable to gamma knife for cyber knife radiation? Is it time to go back on the same chemotherapies? It's switched chemotherapy? Tulum, Epstein or another agent? Do we do opt in? Or do we have a clinical trial for the patient? And one of the main reasons that I'm at UCSF is because of the incredible clinical trials that we have here and the amazing basic science, Um, that hopefully we are going to find better treatments for patients. And so I just wanted to highlight some of those about what we're doing at UCSF now. So one of the major challenges for treatment of glioblastoma is actually getting the drugs into this route into the central nervous system. The blood brain barrier is very tricky. Most of the chemo therapies that can treat other kinds of cancers don't get in the brain because of their size, and so we just can't use them or in order to get them into the brain. They would have such a large, systemic toxicity that it doesn't make sense. So we're really looking into improving drug delivery systems into the CNS. Another kind of passion project is targeted therapy and precision medicine. How can we find the right treatment for each person? And is that a combination based on their genetics? What about improving traditional chemotherapy? Are there ways to make Temodar better less resistant? Can we harness mgmt methylation? How about immunotherapy? And then, of course, viruses and vaccines. There's a lot of excitement for all of these different avenues to pursue for treatment of glioblastoma. First, I'm going to talk about strategies to improve drug delivery. So I mentioned in the beginning the glee Adele Wafer. So that was actually FDA approved years ago were in the surgical resection cavity. You have a way for that. You can put down into the brain tissue itself, um, as its a chemotherapy. Unfortunately, the chemo doesn't really diffuse very far into the brain tissue, so it doesn't really work very well. If you jacked, inject, direct, inject a drug into the brain again, we're not getting very good drug coverage. It stays kind of in one location. We've tried interest, cerebral. Sorry, intra ventricular injection. Unfortunately, the CSF is just moving so much and turns over that the drugs just diffuse away. And so one of the techniques that's really been pioneered here at UCSF is called convection enhanced delivery. And what that is is catheter placement into the brain and then infusion of a drug or a nanoparticle using convection to really increase dispersal of the drug. And this is basically what we see. We do a surgical resection cavity. We have a recurrence. Next to that, we will place a cavity into the, uh, catheter into the brain and then use convection to improve the distribution of the drug over the tumor tissue. And you can see the difference by just diffusion versus a C E D. And so we can actually use many different things in in this technique, whether it's a chemotherapy that's packaged within nano particle, maybe it's pseudomonas and a toxin or something else, or an immunotherapy that we can do So The idea is that you create these nanoparticles that you can now infused directly into the brain. You don't have to worry about the blood brain barrier and or systemic toxicity. Um, and then you can treat the tumor. So we do have some clinical trials that are ongoing for patients using Conduction Hand's delivery. One is a Phase one study that's done here at UCSF as an investigator initiated using Nano Liposome formulation of CPT 11 or relocate T can for patients with recurrent high grade tumors. We also had a Phase two study of M D N a 55 for recurrent glioblastoma. And what that is is pseudomonas and a toxin that is targeted to the Isle of four receptor, which can trigger a apoptosis of the tumor cells. A limitation of these studies is you need a single, solitary, usually super tutorial lesion to be able to place the catheter and get good coverage. And usually it has to be somewhat of a small tumor. If there are large tumors, it's hard to get good coverage, but we're pioneering more techniques to allow for multiple different catheters at the same time, which can actually increase your drug distribution. So I just wanted to highlight one of these cases, so this is a patient of mine, 82 year old female KPs of 90 author really high functioning had a methylated glioblastoma, which was treated with dinner therapy radiation. And we did the hippo fractionated course, uh, for our elderly patients. She got six cycles of Temodar after treatment seven months by, she had evidence of recurrence on her MRI and her hippocampus that you can see with that red arrow. We actually decided to do a C t e d clinical trial for her, knowing that she wouldn't have to undergo any systemic chemotherapy, and she would tolerate it quite well. And this is what it looks like. They actually use intra operative M. R I, and they mix the contrast dye with the infuse it's you can actually watch in real time to make sure you're getting good coverage of your tumor with the CED infusion and for her, she did great. This was her tumor pre CED. Two months post CED. It got smaller, and it basically mounted away six months post C E. D. So this is a really great outcome for a recurrent glioblastoma that has a median overall survival of only nine months. The clinical significance to see e d. Um, like I said, it you can get drugs in without having systemic side effects. You can have low concentrations adjacent to the tumor and everything right at the tumor. Um, and we're really trying to figure out the best ways to do that. And before, we never incorporated real time imaging. Now we're doing that as well as increasing the number of catheters used during the studies. All right, how about targeted strategies? So all cancers are complex. G B m is like that. Like all the others. There are so many aberrant signaling pathways, and you block one and one other one just gets up. Regulated Lots of medications have been tried. Lots of failures along the way. Maybe some glimmers of hope. But we definitely have a lot of clinical trials that are open and occurring for targeted agents, such as targeting the I. D. S mutation targeting DRD two, and are really difficult to treat H B K 27 mutant tuners. We have some targeted agents against or in the IndyCar box, Alice. In our patients with anaplastic tumors and then precision medicine. We've had a big push to kind of understand why each tumor is different in glioblastoma and make recommendations for targeted therapies based on each tumor. So this is an example of this. This is one of my patients who is 68 originally had a grocery reception of a glioblastoma headstand treatment, radiation, chemo, six cycles of chemo and progressed. And you can see um, hear her progression, Um, in two different locations, and we enrolled her on the precision medicine clinical trial. And, like I have alluded to all G b m is not the same. There are different molecular characteristics that give different prognosis different areas of the brain. Um, we see this in different ages. Um, so we really do need to understand more about each specific tumor so we can understand how to treat it. And for this particular trial, if they were a candidate for a biopsy resection, they were enrolled. They had a reception of their recurrent tumor. And after that resection, they underwent U. C s F 500 which is our in house next generation sequencing panel. It's clear certified. It also had some correlative studies with RNA sequencing. Sequencing did some PD X models as well. And then when the U. C. S F 500 came back. We had a molecular specialized molecular tumor board where we reviewed the different mutations and came up with a kind of a personalized medicine approach and did a combination of treatments for patients. So for this particular patient, she had an excellent reception by Dr Sharon Harvey. Jumper Got everything out. Pathology confirmed. Recurrent glioblastoma. This was her UCSF 500. She had to pretty much most of the most common mutations that we see in patients. C D K. Mutation Egypt Um receptor amplification P 10 church trisomy seven Montessori 10 Really a very kind of what we call garden variety run of the mill G B M. We decided to target these two mutations specifically. So her, um, treatment paradigm was CCM you, which is the site of toxic chemotherapy. We gave that in combination with a fat nim to target that e g f R amplification as well as a basic element to target the c. D. K. Four and amplification. She also did great and had no evidence of recurrence, said 10 months on the trial. So again, precision medicine based approaches are important because we are targeting the therapies to each patient. You do get. You do need to have tissue at recurrence because we know that these tumors change in time. The development of mutations. Sometimes they lose mutations. You have to know what you're dealing with. Um, and I think there is a lot of potential to reproduce purpose many agents. But then you have to be a little bit careful when you're starting to combine multiple things together that you're not being limited by your toxicity. Um, and then finally, I wanted to highlight immunotherapy. So tons of work has been gone into for immunotherapy and glioblastoma targeting all sorts of different pathways. Carty, um dendritic vaccines, antibodies, p L one inhibitors tons. We do not have a home run yet. Um, we do have several clinical trials that are open and ongoing. Currently, we do have the polio clinical trial, which is a clinical trial where we inject engineered poliovirus into patients recurrent brain tumors. We do this in combination with checkpoint inhibitors embolism. Um, um, we also have an idea surgical embolism and clinical trial, which is used as new adjuvant Pembroke, followed by surgical resection and also another clinical trial called Zero Farm, which uses an adenovirus to Express I'll 12 after taking oral agent in combination with checkpoint inhibitors. Um, and so this is a quick looking at this clinical trial. We had a 52 year old female headaches, right? Temporal mass again got standard therapy. She actually had an end trek a fusion. So at her first recurrence was treated with the end track inhibitor, which did not work at all. Only two months on that she had another progression. So we enrolled her on the zero farm clinical trial. So this clinical trial, you do a surgery, you inject this adenovirus that expresses I'll 12 after you take this oral activator volatile mix. So you inject it into the brain, they take this oral activator, I'll 12 gets expressed and to give them a checkpoint inhibitor. Um, and so she has been doing great. Um, this was her second recurrence. Her post op scan on zero farm after the virus injection in six months on zero farms, she's still recurrence free. So for the immunotherapy, I think there's still a lot of work to be done. We are now realizing that single agent checkpoint inhibition is probably not the way to go, and it needs to be combined with other forms of immunotherapy. So that's where we're doing it with things like the adenovirus and polio virus. And the other really complicated thing that we see in brain tumors that other cancers may not run into is that there's such a fine balance between the development of inflammation to try to treat the tumor and all of the negative side effects that can happen when there is inflammation in the brain. The brain is in this confined location, and so if it swells too much devastating impact. And so there really is this razor sharp line that we have to tread, Um, for patients on immunotherapy. Okay, So in summary, um, I really, truly believe that we need improved understanding of biology, of tumors to provide more rational approaches to new treatments. I think novel delivery approaches continue to be explored. Lies, treatments and immunotherapy and bio therapy strategies are still being actively studied. And with that, I would just like to thank our brain tumor center. We now have seven neuro oncologists in our group. Suzanne Chang, Nick Patoski, Jenny Clark and Jenny Taylor Mariza, Doris, who both sides glioma as well as is, um, starting our Mets program. And Jessica Sheltie is our newest hire. Um, and then are really incredible surgeons Dr Berger, Dr Theopolis, Dr Augie and Dr Shaun Harvey Jumper. Um, and then also our radiation oncologist. Although their shared between everyone Steve Bronstein and David Rally. And of course, pennies need have really just been so invaluable to our group. So with that, I'll stop sharing my slides. Thanks, everybody. Thanks very much, Nancy. That is just really an excellent review. I learned a lot, Um, and it's great to hear what's going on in some of the other specialties where we just don't hear about anything. We don't have any Q and A's on there. But for those of you have joined in since Nancy started talking, do you put Q and A questions into the Q and A channel? Um, anytime. And, uh, I think, um, for me to start with, I guess just to ask you a quick question, you know, uh, you know, my training on glioblastoma is is really old. So, um, there wasn't a whole lot you could do for glioblastoma is then. But now, with resection and primary treatment, you have a little bit better chance. Yeah, absolutely. So I tell patients at diagnosis that people on average live about two years. That being said, we have patients alive 5, 10, 15 years after their surgery. And, um, we always hope that our patients are going to be one of those. And we do everything we can to make them one of those. And then you always have ongoing clinical trials patients that have sometimes shown quite a bit of efficacy. Oh, absolutely. And then I didn't have time to really highlight all of the newly diagnosed trials. So we also have a very robust clinical trial program for newly diagnosed patients that combine treatments with radiation and chemotherapy. So there's always something going on. We have so many trials open, Um, and so we really do try our best to find the right thing for each patient. That's great. And I know you have really a lot of interactions with the referring doctors and also with, as you mentioned with radiation oncology, which is really important. And then there's also you work with the National Research Group. Also write the clinical trials group. Yes, multiple consortiums that were involved with for different clinical trials throughout the country. Yeah, absolutely. We have both investigator initiated and really large clinical trials going on at UCSF. Right? Well, that's great. It's really good. I don't know if any of the other Panelists have questions for Nancy. Anything you want to comment on and sound like it. Go ahead. Rush were, uh, PBS. I rode the polio vaccine Are going to start that in bladder cancer, actually to what has been your experience with that initially? Mhm. I think it's a very, um, complicated trial because many patients developed these huge immune responses, um, within the brain. And even if that's actually working to kill the tumor, it may actually harm the patient. And so I think it is a pretty complicated trial. Um, they've had a lot of good success at Duke in our hands. I'm not sure we have the same kind of success that they did, but I guess we'll see more as as as the trials keep going. Thank you, right. I mean, it's it's really interesting to see sometimes how we're doing, you know, different kinds of studies across different disciplines. And sometimes we're not even aware that we're using the same kind of technology, So it's actually really cool to hear about it and hear what people are doing. So, Nancy, hopefully you'll be able to stay on for the rest of our discussion. And we may see some questions coming in as we go on. But we'll transfer over now to Steve. Um, and, uh, we're actually right on time, so we're perfect timing. So, Steve is, as I mentioned, our radiation oncologist at UCSF who's very active and taking care of our patients, and we look forward to his presentation. Can you bring everybody? It's a wonderful to be able to join this panel and have the opportunity to talk to you about radiation therapy, which, as you heard, has a major role in the treatment of high grade gliomas. But, uh, today what I want to focus on is the management of metastatic disease, in part because metastatic disease is of great significance across a variety of mostly histological, solid tumor types. But it has very broad relevance. Um, for every oncologist, I have no disclosures. So, um, over the next few minutes, I hope to talk about metastatic disease, but specifically to convey the evolving definition of all of the metastatic disease and cancer patients. Um, I want to, uh, also convey the role of radiotherapy is part of interdisciplinary management of patients with metastatic disease. Mhm. So I'll start by giving a short overview of the biologic basis of metastatic disease, which may have very important relevance in a local metastatic disease. We'll talk about the clinical approach, the metastatic disease and the evolving definitions of illegal, metastatic and a progressive disease. And then very near and dear is the evolving practice with regard to radiotherapy for all the metastatic disease. So we we understand the biologic basis of metastatic disease, um, at a cellular and tissue level. And so, within the primary tumor site, there is a genetic program that can occur within the primary tumor, leading to invasion outside of the primary location, um, neutralization into the circulation and then to a distant site, extra visitation to that distant site and colonization. And that is all a product of a very complex program of both genetic factors, epigenetic factors, local environmental signals that can influence the metastatic progression pathway. Mm. That complexity results in what is understood as a metastatic organa trumpism in that with various tumor types is a selective trumpism for distant sites. That's a function of the primary tumor type, but beyond the primary tumor type. Also the subtype. Genetics. We understand that there's a fair amount of heterogeneity within tumors, and single genetic insult can yield a tumor, which can then proliferate and create sub populations. And there can be a fair amount of inter tumor inter patient heterogeneity and that can arise from the genome from the transcriptome proteome as well as epigenetic influences. Mhm. And what that yield, for example, of breast cancer model here is that within a particular tumor type, you can see this trope is, um, uh, that's associated differential gene expression and this is what we end up seeing in the clinic. And this helps, uh, and continues to help inform our tool set as to how to address this disease. Radiotherapy has been used historically quite extensively in the management of metastatic disease. So amongst all radiation oncologists, about half of radiotherapy is currently delivered with some type of palliative intent, generally in the advanced or metastatic setting, and within that about three quarters of patients with advanced solid tumor types, such as breast, lung, prostate cancers with very high incidents in this country, um will ultimately develop bone metastases and radiation as a focal therapy can help address these lesions. And historically, this was largely to address, uh, symptomatic lesions. Now there's a tremendous variation in practice with respect to the particular technique, the dose, the fraction ation pattern and the target delineation. So it's somewhat like here, symbolically rolling the dice. There's a high variability in practice and providers, and it's it's expected because there's really a lack of high level evidence, Um, despite investigations, uh, as to what is the ideal or optimal approach in these patients, and in part because we all have a desire to personalize the treatment in the particular clinical context. But by way of example, showing historically in bone disease, Um, a variety of randomized clinical trials have been undertaken using different types of fraction ation different doses, um, directed largely a pain relief, but progression was also noted, and there is no significant differences that have been found. Uh, in in these various clinical outcomes may be slight higher rates of re treatments for short course therapies. Um, but overall, um we don't see uh, distinct patterns of outcome as a function of the intended approach. Now, of course, there's many confounding factors which influence outcomes and make the study very challenging. So we rely on evidence based societal guidelines that help inform our practice, um, and historically has shown highlighted here. We favor shorter course lower dose regimens and in part because its ease of delivery. There's less technological sophistication in many cases required to give, uh, more gentle, lower biologic doses. Um, that can be associated with more minimal or modest acute toxicity, but this can have the consequence of less durable local control. But what what is the actual clinical consequence of that? Well, what's been increasingly appreciated and when I say increasingly, I mean over the past several decades and this is not new is that there's a spectrum of metastatic disease on presentation. Uh, the notion of the metastatic disease burden in some cases has been associated with outcomes, and that's shown here in more recent studies. But even historically, we understand that in some instances, both the number and location of metastases can influence outcomes and with coined the term, although many uh, illegal metastases from the Greek, which means few versus policy. Many Matassa seats now in practice, we generally describe this almost biggest stopped. We look at the radiographic imaging, but there's no clear thresholds, and you'll see that throughout this talk. There's a lack of consistency around quantification. Um, and it's part of this general impression by which we've approached studies of this This phenomenon. So shown here by example in prostate cancer, metastatic prostate cancers continue of metastatic disease. Um, localized disease intuitively favors a local approach, although not true in all disease types of star comas, Um, neuroblastoma is now under consumers that have high rates of micro metastatic disease at presentation and require systemic therapy even for seemingly localized disease. Radio graphically, um, and so classically disease burden is defined by, um, imaging. And so, as we've evolved and have more sensitive imaging, it's allowed us to be more accurate to the estimation of disease burden. But with regard to interventions, the real questions are thematically. What outcome is meaningful in this setting? Um, and what outcome? Not just in and of itself, but as a function of the metastatic disease burden. Yeah. So the concept of metastatic disease was formally proposed by Samuel Hellman and Ralph Wekselbaum at Chicago in 1995. The notion of the state between completely localized disease and widely disseminated disease was reflected upon, um, in the literature before that, in the context of, uh, treatment paradigms and protocol generation, The key elements of their hypothesis or their proposal is that cancer prizes of biologic spectrum. You have localized disease, you have metastatic disease. And then there exists these intermediate states, Um, and somewhere within those intermediate states, maybe right beyond localized disease. Um, there are some patients that are so effective that they could be amenable to a curative therapeutic strategy. And this is very striking to, um, consider curative approaches in metastatic disease. Yeah, well, um, there is data that supports this algo metastatic curable disease hypothesis. Um, there are a number of surgical studies in the literature from the nineties. Uh, this one's shown from patients with colorectal cancel cancer with lung metastases undergoing lung resection or wager section. And what you can see is that there's a very long tail to these survival curves. Um and so it's It's very striking that you can impact survival in the metastatic setting with local therapy. Um, and so you can see that there is a substantial of our patients that tell these curves with survival of 2030% at 10 years. But also it appears to function again in retrospective setting as a function of the number of metastases. So the disease burden may impact this, and this is observed not limited to colorectal, but sarcoma, renal cell cancers and primary lung cancers as well. So akin to surgery, um, in a very timely fashion. Radiation therapy is understood to be a powerful local control modality. But over the past several decades, we've had technological advancements in imaging and our ability to use image guidance to target lesions, increased computational power and precision delivery. And this has led to more oblate ivo radiation techniques. So as compared to traditional protracted what I call gentle fraction nation, uh, techniques this form of radiotherapy, specifically, steri attacked radiotherapy also, uh, known in short as stereotyped body radiotherapy or stereotyped of a blade of radiotherapy. These are the technical names. Um, uh, it's, uh, it's a blade of in nature. It's akin in some cases, a surgical resection as a function of very high biologic ghost, generally given over a short, uh, number of sessions, sometimes as short as one session, Um, but what I'll show you. It's demonstrated excellent local control and has steep dose gradients to minimize radiation deposition to regional uninvolved tissue. And we recognize that this can be applied to the elbow metastatic setting towards more aggressive and durable local control. Now there's a number of technologies that can be used to deliver this, including CyberKnife gamma knife. But now you've been general linear accelerators in advance to the point that they can deliver this type of treatment reliably. Historically, these have been used in the treatment of brain metastases as early as the fifties and sixties, as well as, uh, primary lung lesions in patients who are otherwise non operative. And, um, we've demonstrated there's excellent late rates of local control. But when we look specifically the treatment of metastatic disease now, in the past decade or so, um, we've transitioned not just to bring in lung, but to additional sites to lymph nodes to spinal type treatments for tomorrow's final treatment. And a number of these retrospective and early phase institutional experiences have demonstrated great local control and, importantly, safety with this dose escalated on type of therapy. Now I want to point your attention to a few seminal studies that have arisen in recent times. And, uh, this first one is by Daniel Gomez during some at M D. Anderson, which is a study that was done in a logo. Metastatic lung cancer. So it's a Phase two randomized study. 49 patients with patients that had 123 metastatic sites and the randomization was to maintenance, therapy or observation versus, uh, local therapy. So local consolidated therapy and that could be in the form of surgery or radiation. Um, and this study was actually closed early due to a significant benefit observed in the local consolidated farm. And that's shown here is a benefit in both progression free survival as well as overall survival. Um, and this in the modern era is very compelling because this is demonstrating in with high level evidence, um, the role of local therapy, potentially in extending life in patients with metastatic cancer. Now concurrently, um, not limited to a lung cancer was the saber comment trial run by David Pama and this, uh, include a number of malignancies um that was included, patients up to five metastatic lesions. And the randomization was to standard palliative intervention versus the standard intervention plus stereotype trick radiation. Um, and this also strikingly showed a significant improvement in median overall survival as well as a progression free survival. Now, notably in this trial, as I mentioned there, diverse patient disease characteristics and had a well representation of different primary histology is, um, representation in terms of number of metastases, location of metastases. However, there was a significant rate of high grade toxicity given this treatment. So 4.5% of patients actually or three patients died during this. It was attributed to the actual radiation paradigm. Nonetheless, uh, we've moved ahead as this was positive in terms of extending survival. Um, and now, as we've done in the brain metastases literature, we are expanding our definition of what comprises metastatic Olivo, metastatic lesions. And so, um, that there is now the saber comic 10 trials to randomized phase three, um, similar to the the prior saber trial. Um, including stereotyping radiation up to 10 metastatic lesions. Um, and there's been some refinement in terms of the dose infraction nations based upon the review of the prior saber trial to maximize safety Now at the same time again, this has really been an exciting year or a little over a year in the in the realm of logo metastatic disease with regard to ago metastatic prostate cancer was a stomp trial was reported included 123 metastatic lesions in the recurrent setting, which include lymph nodes or distant metastases, and these patients after imaging. The imaging in this case was Colin Pet CT. Um, there are more sensitive imaging techniques available, but in this instance, patients were randomized to metastasize directed therapy versus observation and androgen deprivation therapy. Uh, and the results of this trial showed in the intent to treat population there was a benefit with respect to engine deprivation free, uh, survival. Uh, and, uh, there was no difference in terms of castrate resistance, uh, free survival, but still compelling. I'm showing that a aggressive all the aesthetic intervention can influence outcome. Uh, in addition to the stock trial was the Oriole trial, the phase two randomized controlled trial of 123 metastases in the absence of a d. T. The recurrent setting just stereotyping radiation alone and this used conventional imaging as well as potentially a more sensitive imaging modality of PSM a pet. Um, the results of this trial demonstrated, uh, improved biological progression free survival as well as distant metastatic, uh, free survival. But increasingly, what we're seeing are interesting biologic correlates. And one of these includes, uh, the, uh, presence in the stereotypes radiation arm that did not show progression of disease, an increase in the baseline clinical T cell population. And this is a provocative and I'll speak more on the center moment. So as we look through other sub sites, including breasts, the energy big cooperative group is looking at, uh, the use of local metastatic disease directed therapy in patients with essentially recurrent metastatic breast cancer that have been, um, treated with a first line therapy over a year without evidence of progression. There's a phase two component look at meaning progress, tribute, survival and transition to phase three for median overall survival. We also see this in lung cancer as well and big cooperative groups, um and so this is being applied across a number of disease sites. However, there's a lot that yet remains unclear, and this is exciting for us as radiation oncologist. Because now we have a whole new line of inquiry to explore. Including, um, what is the optimal dose infraction ation? How can that be a customized particular histological at their subtypes? Um, what is the appropriate number of sites of metastatic disease and started at 123125 And now we're looking up to 10, um, lesions. Are there biologic markers that can have a prognostic or predictive, uh, influence in terms of outcomes. What's the timing? In terms of when we should be acting up front in the presence of synchronous or attack Ernest lesions the sequencing. This is very important in conjunction with our colleagues and medical oncology in terms of synergy of treatments in the era of new immuno and targeted therapies and ultimately, again being personalized. What is the cost of effectiveness of these, um, interventions? So very briefly, I'm just going to mention, um, you know, some of the trials that have been done, including this phase one dose escalation trial. Um, ultimately, this showed a very profound local control, about 95% but no difference in outcomes by different dose fraction nations. Well, we participated in another clinical trial that was recently reported. And this demonstrated, in fact, that a more powerful biologic dose approach of giving 24 gray in a single fraction for, um select patients actually resulted in improved overall, uh, local control, both at two years and three years. And it's important to note that now patients in this era of improved therapies are living longer, Um, and so that we are looking at outcomes at two and three years. Um and notably there is no difference in toxicity with these. Various regiments was also found to be a decreased incidence of additional distant metastases, which speaks to the seed and soil hypothesis of metastatic disease can recede, uh, other additional metastatic sites. Now, I just want to say very briefly about the interaction between this type of radiotherapy and other types of immune mediated therapies. And so there's been a number of early studies that have been done, including just a post hoc analysis of the keynote one study that suggests the potential benefit of radiation and combination with immune checkpoint inhibition. The idea is that high dose radiotherapy can lead to increased release as Jenna release that you can improve oxygen presentation and maybe t cell infiltration. So ultimately, radiotherapy may enhance the effects of checkpoint inhibition. So we are really now asking Is there a role for this in this particular question, study was asking in the role in returner advanced non small cell lung cancer. Um, and in this case, uh, technically, the trial, the trial was negative. Um, uh, it may be a function of the trial design, but we continue, uh, investigations into this. Now, I will speak very briefly, um, to, uh, the sort of extreme form of the idea of a local therapy having a systemic response, which is the ABS couple effect. This slide has been shown a number of times the sort of the seminal evidence of this in practicum, which was by, uh, Mike possible, and the treatment of a patient with metastatic melanoma where you can deliver radiotherapy to one side and then see a response at a distance site. And this is thought to be immune mediated. Now, investigations into this have demonstrated that in fact, when we look at patients who are undergoing these types of trials and the responders, we often see a signature. That's the dependent upon lymphocyte activity on a lot of it's work done by Civil Formenty and the disciples in New York. Uh, further resolve this and understand that this may be related to Colonel T cell population Dynamics. Um, and cytokine specifically interfere on signaling, but it still remains elusive to a large degree. Um and, uh, with regard to this, um, you know, there's a number of studies that have been published this one just recently by Sean McBride Morrison Catering I think the most recent issue of J. C. O. Where, despite, uh, the efforts around combinations of checkpoint inhibitor therapy and Syria tactic radio therapy for recurrent or metastatic disease. It's not something that we're reliably observing, but we remain steadfast in tweaking some of the biology. And I think as we understand the biology, we may get to a point where we can more reliably, uh, generate this type of effect. So I just want to also note this work done by one of my colleagues in the department. Julian hung. So in the interim, you know, outside of the biologic markers which were seeking, we can use clinical factors to help predict outcomes. Indelible, metastatic disease. And so this particular large recurring, uh, partition analysis. Um, that was done looking at histology. Um, time to metastatic presentation. Number of metastases and age was able to stratify patients in terms of outcome in a variety of histology ease. And I'll just leave you with where we are right now. Um, which is, you know, in this somewhat large UK study looking in a modern cohort from 2015 to 2019 patients with limited disease, um 123 elbow metastases using stereotypes, radiation in practicum. Um, we are seeing that patients are enjoying a relatively long life with the overall survival 92% of one years, 80% of two years and very limited toxicity. So this is the state in which we exist now. We still have a number of questions. What we understand is that patients who have good performance have status who have limited amounts of metastatic disease in some favorable sites, that they may respond very well and we are able in a combination with more modern systemic agents, which is not to be underappreciated, can potentially improve symptoms, but also the disease free survival, as well as overall survival So this is very exciting to us. And we have a number of trials now, uh, opening at UCSF around this as a function of various primary disease. Histology is, um so we hope to continue to contribute to our understanding and really optimize this, um, for our patients. So with that, I'll thank you, and I'm happy to participate in discussion. Thanks very much. Steve, that was amazing. Really great discussion. And an area I think of great interest is treating a Liga metastatic disease where there's a lot of studies going on. As you pointed out, looking at this now, certainly in breast cancer, I think I counted there were five or six ongoing trials, which is amazing, right? Canada, The U. S. You name it. Um, probably more than that. But my question to you to start is just to what you do with the patient now. So what are you thinking about? Um, if when you see a patient like this, uh, and we don't have a trial available now. And do we have an ongoing trial? One of the questions that came up or what are the UCSF past and current contributions to S B R T saber of the ligaments? Absolutely. Um And so I think we still handle this, Um, a patient by patient, I mean, a personalized level looking at the disease burden. We are at UCSF, an institution that has phenomenal diagnostic imaging technologies. And all of this is really right. Now, a function of diagnostic imaging and emerging biologic markers circulating tumor cells circulating tumor cell DNA to really estimate What is the systemic disease burden of patients? Now, we've contributed a number of ways. A lot of our work was in the what I would call the original logo metastatic setting, which was brain metastases, and I didn't spend much on that. But initially, the the initial you know, level one evidence for overall survival. Improving with metastatic disease was patients were receiving whole brain processed area. Tactic boost that Syria tactic, boost um, in level one. Evidence of conferred a survival benefit. So we have a long standing history in terms of approaching this in brain metastases. We had contributed patients to that dose finding study with Memorial Sloan Kettering, and we have a number of trials opening now both in the GI Space and now with my colleague who's focused on medicine disease. Lauren Beretta um, opening to try to, uh, personalize the care and delivery of metastatic disease. One of the benefits, uh, is that with these approaches were able to do relatively short course. So this is great in the sense that it's less disruptive to patients who are undergoing systemic therapy because we can deliver very focal high a blade of doses in a relatively short period of time. So we're underway with a number of trials to be able to, um, stratify patients accordingly and further with our dose finding techniques. Yeah. I mean, I think that, uh, the whole area of treating a Liga metastatic disease really came about because we have S P R t uh, and it's kind of interesting, because before that, we call it cherry picking, where we took out metastatic lesions. But now we could do this really focal radiation. It's made a huge difference. And so the one of the questions is the relative benefits of focal radiation. I know you and I talked about this a lot. You always panicked when somebody wants to do two weeks of external beam radiation because you cover such a bigger field. And my sense is that there's a lot more marrow toxicity from doing that. Which, of course, then limit subsequent treatment. Absolutely. And I agree that is a profound consideration, really. The approach, The metastatic care is truly interdisciplinary, and so it's important that what we can offer in terms of local therapies, it's not disruptive to the larger picture of cancer care. Um, now all that being said, you know, we have been able to show and I can talk about this today. There's also have been a number of trials recently emerging that show these those escalated very tactic approaches can benefit even in a symptomatic, uh means and so we can achieve greater rates of symptom control if not durable local control for these patients. Uh, and it's important to consider that when we think about quality of life, uh, in the context of cost effectiveness so we can offer a therapy. Um, that is a very technologically sophisticated but ultimately can be cost effective because of the profound clinical benefit, both from a patient centred, uh, perspective of quality of life, but also for local control and potentially improving overall survival. Like I said. There's a lot of excitement about this because, uh, we are in a place where we're really just trying to Thailand and optimize this for our patients. And I think it's true overall, even when people don't aren't, uh, really candidates for Liga metastatic type treatment when we do radiate, for whatever reason, you know risk of fracture spinal cord issues. Having that technology, I think, really has been a boon for patients. And even though often I know it can take some time to get insurance authorization for this right, that is an issue. Although I think with the public the emerging publications, the indications are becoming larger as well, and so it probably will help facilitate. But there is a message in that as well, and that it helps. And we have a great relationship specifically in this regard that those patients get put on our radar quickly because we can address that upfront issue with regarding authorization, um, and so that we have enough time to do what we need to do to try to obtain authorization and then move forward with the treatment. So the last question before we moved to robotics is a tough one. I think it used to be. You know, we heard these conversations a lot of times for breast cancer when I'm on panels, Is that you know, we used to be We thought, Well, you can only do so called gamma knife or whatever you're doing. S p r t cyber knife for, you know, for brain lesions. Right? Or it had to be smaller than this or it had to be. Then it was five lesions or aid or whatever it is. But is there a true upper limit now? And when do you think about still doing a gamma knife type approach versus whole brain? So it's a great question. Um, and that is a question that has also been increasingly addressed in studies regarding the number. And so we have a number of studies looking, comparing whole brain or a modified whole brain type regimen with Sarah Patrick Radiosurgery now up to 15 or 20 metastases. So we're going to get that answer actually a randomized control fashion. But the way that we approach it currently is from a practical standpoint of understanding, um, what we see on imaging as a reflection of the intrinsic disease burden. So, um, if we think that a patient truly has a limited number of metastases, whatever number that, maybe it could be 20 lesions. Um, and we can offer a durable local control with radio surgery. We like that option very much. What What we want to do is not miss a window of opportunity where there is an additional burden of micro metastatic disease. And we didn't offer more comprehensive therapy. And then, um, they quickly recur or even develop left a manageable disease. And there's a question still to be answered. But it's that therapeutic window of opportunity that we really think about that we're not under treating a patient. Yeah, that's great. Really helpful. So it's good for people to know, actually, that, um, it's really can be individualized to the patient. Uh, now I think we'll move on and we're going to talk about robotics. Very exciting with Raj Pruthi, who's, uh, in urology and talking about really fascinating a new area. Great. Thanks. Hope And thanks to everyone. Uh, so I want to talk to you and spend the next bit of time talking about robotic approaches to bladder cancer surgery. This is a quote from a textbook from our kind of classic textbook called Campbell's Urology, which is the mainstay written by Campbell himself about 70 years ago about just reflecting their morbidity of this operation. Uh, with regard to bleeding and the very high complication rate. And and in some ways, uh, Campbell was right. The complications for radical suspect me are very, very high 90 day complication rates you can see in two thirds to three quarters of the patients. The readmission rates are 27 up to 42% in some sear Medicare data. And in fact, readmission rates for this surgery are higher than a salvage ectomy and pancreatic. To me, uh, so again, it is one of the most morbid operations that we do. Um, but it does remain our front line therapy for invasive bladder cancer, and you can see a 90 day mortality rate of 7 to 11%. And again, half of these readmissions and mortality will happen 30 to 90 days, half within the 1st 30 days. So these are obviously daunting statistics, but I think provide for us a challenge to improve the quality of care for these patients and outcomes. So broadly For these patients with invasive disease, there's a couple of strategies to improving the outcomes that we're undertaking. One is refining multimodal therapy, so improving peri operative chemotherapy That's a German neo adjuvant, typically platinum based and development of new agents, especially around the area of immunotherapy. The other is more on the surgical end, improving peri operative outcomes, including clinical care pathways. So that's things like eras and how we kind of manage patients before, during and after. Uh, and we've come a long way in the last 10 15 years in this regard, as far and in addition to is refining the role of robotics hysterectomy. And that's what I'm going to talk about today is, is the role of robotics hysterectomy. So robotic Suspected Me has emerged from our growing experience with robotic radical prostatectomy, which has essentially become the mainstay of treatment for localized prostate cancer and patients undergoing surgical therapy. And, I think suspected me robotic hysterectomy provides a viable alternative for some of those patients. Benefits a minimally invasive surgery. We've seen it time and time again. You see, on the left here, Cole assist ectomy, going from a large kind of right sub costal incision to laparoscopic approach. Same thing with an IFR ectomy again, rather than a large flank or sub costal incision to laproscopic. And the same occurs for suspected me. And you can see classically here on the left this kind of from the typhoid to the pubis type of incision versus, uh, laparoscopic and robotic incision, which is shown here. And I'll talk a little bit about that. Um robotic radical suspect me. There are some potential benefits. Obviously, that's significant reduction in incision and the pain associated with it. Less blood loss. It seems to be less fluid. Imbalances involve manipulation. Uh, by being a lesser extra creative approach, um, potential concerns. You know, bladder cancer is a deadly disease, a potentially unforgiving disease. So nothing we should do. No surgical approach should compromise the oncological efficacy of the operations. And we do have to think of other aspects related to this. What is the learning curve? The overtime? The cost for this isn't just a surgical stunt. We UCSF have made significant contributions to the literature ranging from the original description of the operation in males and in females and everything ranging from cost analyses, intercultural diversions and a randomized controlled trial, which I'll talk a little bit about, is a very aware undertaking. And surgery is to actually randomize patients to surgical types. Uh, this is one of the original descriptions the first descriptions that we partnered with intuitive on. This is when I was at the University of North Carolina on, uh, robotic radical suspect to me and in some, uh, text books. Also then emerged with our contributions on robotic surgery of the bladder. And I want to approach this for everybody in terms of value importers, definition of values, which is outcomes divided by cost. So are the costs and doesn't have to be financial cost, but the cost of undertaking something. If it goes up, that's fine. But if the outcomes to go up by a greater proportion, that adds value. So how do we evaluate outcomes and surgical quality and value and bladder cancer? And I'm going to address this in terms of three different buckets on CA logic, outcomes, morbidity and other meaning costs. And we'll touch on that and we're gonna try to stratify whether there's an advantage for robotics, a disadvantage or there doesn't seem to be any data driven differences. So let's start with oncological outcomes. I wanted to share this with you because we'll go through some of these. Uh, this was a report by a collaborative group report looking at what are what are the optimal outcomes for a patient undergoing what is proficiency in undergoing a radical suspect? Tamia, ranging from margin status to lymph node yield and so forth here you can see in this sort of forest plot soft tissue margins with soft tissue margins have been shown to decrease survival. Um, no significant difference in rates and open versus robotic approaches. Uh, to this and in the statistical analysis, this doesn't really favor one or the other. So there isn't a compromise at least two soft tissue margin rates for robotic hysterectomy. In fact, here's some kind of robotic, uh, kind of, uh, pictures showing you really can get around the bladder. And in fact, it's not a top down surgery anymore. Here on the right side, these are the bladder Pericles, whereas the most common sight of the soft tissue margin and you can get well around that here with the stapler, rather than look at a top down but actually have a great perspective. Another metric is lymph node yield. Uh, this is a randomized trial that we did a number of years ago. Looking at again, open versus robotic. There's a very timely trial because at this time patients robotic approaches to suspect me just weren't done. So patients didn't come in with a specific preference. I can tell you in prostate cancer they come in and they want the robotic approach and they they've educated themselves. But in bladder cancer, they didn't have this. So this was an opportunity for us to in a RGB approved prospective randomized trial evaluate them. And this This looked at length no yield as a non inferiority. And in fact, there was no significant difference in lymph node yield between the two. Again. One of the measures of that collaborative group report a number of other studies here K series and so forth. Um, no significant difference in lymph node yield. Even the collaborative group report by her was 12.5. But if you look at get the forest plot, there's really no significant difference in length, no deal, and then the most important outcome is obviously survival. A few studies here with follow up of about two years, which may seem a little bit on the short side. But it's important to remember in bladder cancer that 86% of recurrences happened within the 1st 24 months. Uh, and recurrences are often deadly, So a two year time point is a statistically valid one. No differences in survival on the Friday these studies. Another study looking at outcomes here. No difference in recurrence, free disease specific or overall survival between either approach. And I want to mention a razor trial, which is a prospective randomized, NIH sponsored surgical trial that took sort of our concept trial. Single institution became multi center, multi surgeon trial, recently published and land set, originally published in Lancet and most recently last year in Journal of Urology. Showing again, No difference in recurrence, UH, free or overall progression. Free survival in either approach. So I think we're again on ecologically, there's not a winner or a loser, and that's important for any new technique. Again, it's it's There's not a lot of salvage options for us. Let's talk a little bit about the peri operative outcomes of associated with surgery and When we think about this, we think about things like blood loss and transfusions, operative time, a patient under anesthesia, length of stay and importantly, complications which we know can be very high. So this is just a chart showing a large number of kind of series. We've contributed a few of these theories here, as you can see in 2007 and 2000 and 10, uh, looking at complication rates, Um, break these down blood loss. Looks like that there's about, on average of these series and meta analysis less than 500 ccs blood loss with a robotic approach and and odds ratios significant reduction in transfusions. You can see here clearly on the forest plots. There's a clear benefit and an undoubted benefit of less blood loss for the robotic approach. This has seen time and time again with kidney cancer surgery with prostate cancer. It's clear, and certainly with bladder cancer as well. Um, operating room time is often a surrogate for maybe operative, you know, morbidity or involvement in a bright In the prospective trial we did, we saw a difference of about 45 minutes. Uh, overall, when you look at men analysis. It's about 74 minutes. So, on average, about maybe an hour longer to do a robotic approach, and you can see this in the forest plot. So I think, in a sense, this is a disadvantage. Robotics. It takes a little bit longer to do a robotic surgery than an open surgery. Uh, now this. This may or may not matter, and I think this is speaks to patient selection, a patient who can tolerate longer operation by an hour. This is, on average, Truvada a 68 hour operation as low as four hours. But obviously, uh, and adding an hour can have potential complications. And for the older patient with maybe cardiopulmonary disease, you want to get them on and off the table. Pain and I showed you the incisions and decreased decisions, and this certainly translates into less narcotic use and morphine equivalents. Here she had seen a couple of studies, which is an advantage for the robotic approach, and that's not really a surprise length of stay in a overall and meta analysis about at 1.3 days less for robotic approach. Um, and in fact, in 10 non randomized studies, the mean difference was about three days in the randomized studies. It wasn't statistically significant again. And that small randomized study was about 30.9 days. But again, maybe the small end there wasn't a significant difference. So I don't think we're seeing some evidence, maybe of a lesser length of stay with robotic approach. So this, you know, with some qualifications, maybe a little bit of a benefit for robotics. Importantly, complications for, uh, robotic suspect. To me, this is sort of our original study of, uh, 100 patients. Another study published, uh, shows that the robotic approach was an independent predictor of lower complications versus open, um, factors which predicted higher grade complications, higher blood loss, more intra operative fluids, which usually is length of operation older patients. Um, this is again the forest meta analyses, uh, showing fewer complications, Uh, in the robotic approach. I think this is a clear advantage of robotics mastectomy, and next I want to touch a little bit on beyond the peri operative time period. But in the short term quality of life looking, a study, we did looking at the fact bladder and the SF 12 in patients, a two year follow up There was no difference between any of the domains between the fact and the SF 12, except for UH, interest in sex and ability to obtain and maintain an erection. Both improved for the robotic approach. Other studies looking at again, a few of the other quality of life measures. One showed improved physical well being at six months other, longer term follow up. No difference between the two approaches. So I think when you look at long term quality of life, if you're two years out, there is probably no difference between one approach or the other. Maybe a benefit in the short term when you're recovering. Uh, maybe a improvement in sexual function with robotic approach. The last thing I want to touch on is costs all important. And when we talk about any new procedure these days, um, financial costs with robotics, there's sticks to our costs. They so our costs, robotic investment, instrumentation, variable costs and hospital costs, including transfusion costs. In my work that we've done looking at costs and a variety of different things, I can tell you when you look at this, this is really challenging, trying to figure out what costs are it really depends on where you draw the circles, right? If it's around the operating room or in the hospital, stay. Is it in the recovery of the patient and the convalescence and back to work? So where again those circles are drawing can really impact it. Looking at the randomized trial we did, which was a perfect example of looking at that, uh, Perspectively, there was no significant difference. Actually, between the open and robotic approaches, um, you can see here the our fees are higher for robotic by some of the post operative costs or less. Another study by Martin from the kind of show that the robotic or costs were more expensive. But, uh, total patient costs were less primarily due to reduced length of stay. Another study by Jim Hugh looking at kind of sear data showed no difference in cost between the two. So I think there's an uncertain impact. You can kind of see it both weigh between open versus robotics, so we'll call that kind of a draw. So I've kind of broken this down into things, have comparable benefits and negative. And let's go back to that porter kind of equation of value, so outcomes that are improved are shown here. When we talk about this blood loss paying length of state complications, the cost might be or time, which again, taking aside physically the cost of the surgery. But that is the cost of a patient being Noor an hour longer, even the cost of the surgeon or an opportunity cost for another patient not getting cared for, but to me, the extra hour with these benefits. I think this certainly provides what I would say value to the patient and is a worthwhile kind of, um, pursuit. I think we we did the first. I did the first robotics suspect me. Now it's 15 years ago in 2000 and five. So we've come up a long, long way, and I think it's It has proven itself so again in, in my opinion, I think it does add value to the care of patients undergoing radical suspect to me. And it's something that we're doing here at UCSF. I'll show you a little bit of sort of videos of what does it mean when I talk about kind of robotics? So this is our robotic view where we're starting off the case here. We're tagging the terminal ilium. You saw a little bit of the appendix there. I'll move us along here. So here you can see the ureter kind of coming through where it attaches into the bladder. So one of the first things we'll do is kind of score and identify and isolate the order here. We're getting around the order. And again, rather than using our hands were using the robotic instruments to work our way down Ah, to the bladder. And then we can actually isolate there and then come in with a clip, Laproscopic. So again, all of this done laparoscopically. Another nice thing about being robotically is the your orders can be de Vasteras. You can do most of this towards the retro peritoneum and maintain the blood supply. Now we're going to do the same thing here on the right side and identify the order. And take that down to the bladder. Um, and then here you can see the Foley catheter here in the middle. So let's I want to show you something else. Here, too, in the dissection. So this is dissecting around the bladder? Uh, identifying kind of the this is the bladder, Pericles. And again, this is the area I mentioned before. The largest soft tissue margins occur here, so we're going to be able to kind of identify that pentacle with straight on view. Um, And here you can see our stapler coming in to be able to divide those particles. Um, and that's kind of how it looks. And then we can divide it and clipped. And then we're going to do the same thing here on the other side. I just want to give you a view of what does that look like? This is what the patient looks like after, rather than that again, stem to stern incision, a much smaller incision. And this is with doing the diversion on the outside of the body. Um, this is kind of what the recovery looks like. This is a patient who had a neo bladder, Um, few other kind of images of what that looks like, uh, in the recovery. So I think what we're seeing is I kind of finish up here is an increased worldwide experience with robotic radical hysterectomy. We're seeing longer term oncological outcome. We do now have a multi institutional randomized controlled trial. So the highest level of evidence showing some benefits the future directions are inter corporal, urinary diversion. So that's actually doing the illegal conduit or the neo bladder within the body cavity and single port surgery. I'll touch on that. So I want to show you just a little bit of a video of what it's like to do the urinary diversion, the Elio Conduit internally. So here we can divide the bottle. Mesen Terry here and then here. We're actually re approximating the bowel in a side to side functional end, end way again rather than doing this outside the body were doing it inside. We've connected the bowel there, and then we could close the bowel and restored about continuity. Now we have the yarder here and again. We're not pulling this outside the body, so we actually preserve the vascular charity of the blood supply there. And you can see we're kind of putting our stitches there and can tie down the order to the conduit. This is the case. It's a neo bladder and kind of so that up there as we close that and so this is kind of what it looks like the question. We are faces in the mail, for example. We have to take the bladder and prostate out. Where do we take it out from now? We've done everything internally. One option is to actually the estimates site. I don't like to do that because it can stretch that site. The other is often by increasing this incision. The other thing I've done is, uh, impatience is this is a lady who has undergone a neo bladder. And what we did here is, uh, actually took out this specimen through her vagina through a poster trans vaginal incision. And you can see she's had a neo bladder here. Quite a difference between a decision that again goes from the site for you to the pubis. The last thing I want to touch on is something we're doing very new here at UCSF is single port robotic suspect to me. So now we're using this new robotic instrument That's the single port robot. So this isn't connected in the body. So rather than a multi port, this is about 2.5 centimeters, or about one inch and goes in. In fact, we were the first one to do this operation west of Chicago in the first and in California to do a single port robotics vasectomy. This is a little bit in a diagram of what it looks like for prostate cancer. I'm doing all of the prostate cancer surgeries by single court extra parent Neil also. So it keeps us out of the bowel cavity and helps in the patient recovery. And, uh, this is kind of the patient that had a suspect to me, for example, is just one port here and that incision to do the diversion here. And I'm gonna show you kind of this here. Um, the this is kind of from the intuitive folks. But you can see here kind of the single port robot and what it looks like. And the instruments kind of come out through this cannula and it's a again, a one inch or 2.5 centimeter cannula and arms kind of spread out within the body. And you have control here that can be scaled movements up to 10 to 1. The ability to flex the camera that you can see here, I think, is a real advantage, especially in the prostate cancer patients, where from a nerve sparing standpoint. You can really look around corners. And this is as the surgeon, you can control the masters and actually rotate around 360 degrees. And this is just sort of a little bit of a showing how you can go down this very narrow tube and do your operation in a very narrow, narrow, narrow space. And again, you can actually flip your camera around to make it easier to operate in what looks like it's, you know, you're here, you're you're truly operating upside down. But from your perspective, you're used to operating right side up like this and allows you to do that with that computer interface. So just to show you a little bit of kind of what that looked like, um And then the last thing here is, uh, people can email me and unhappy at this point to pause and take any questions people may have Thanks hope for inviting me. Thank you. That was just a I like your picture too. I want that picture. But the, uh that was great and so interesting. And I really adored the picture of the device because it looked like everything you got from a science fiction movie. You know, one of those little creatures with the eyes and the hands, you know, very cool. So really excellent presentation. It's so interesting. One of the questions that came up from somebody was about value and outcome, and they comment that they enjoyed your talk. If you simply define value equals outcome over cost than an infinitely large value would result from zero cost or do nothing. Approach, I think, result in a I hope this is not what you meant to, they say. So maybe you could comment a little bit about the value equals outcome over cost. I mean that that's yeah, that's a general construct not meant to be a denominator of zero, right? I mean, um, and there's certainly cost. It's not all financial costs, but there's a cost in doing nothing for a patient, right? There's quality of life costs their survival costs in that, too. So that's great. Yeah, sounds very reasonable. And then is everybody a candidate for robotic surgery? Or there are people who aren't very good candidates. And, uh, when you make this neo bladder, how do you decide when it's external versus internal Yeah, so thanks Hope. The, uh, that's an important question is everybody is not a candidate for this, and, you know, it's the concept of just because you have a hammer. Everything is in the nail, right? I mean, it's you have to You have to be thoughtful about this. The when we do this robotically in bladder cancer, if anybody has ever seen it, it's a very steep trend. Ellenberger head down position and it's a little longer in the ore, so I tend to I do it for most of my cases. But if I have an older patient with cardiopulmonary issues, you know they may not tolerate the insulation and that very well. So sometimes there is a value to being on and off the table, so to speak faster when you can ventilate them better and so forth. So this really is. It's like anything in surgery, I think I say it's our trainees, you know, part of being a good surgeon. This is just what you do in the operating room, right? It's judgments you make before you even get there. Who to operate on who not to operate on and what kind of operation to do the same for anemia. Bladder. I think we will do. Um, we will do some of these. And again, if a patient can tolerate it, even a decision for a neo bladder or not, there's a lot that goes into that, Uh, it's not. You have to be quality of life. Studies have shown at the end of the year, whether you have a neo bladder or a conduit, it's actually the same. Uh, because it's It's, I think you have to counsel Neil Blatter has their own issues with it, right? It's not truly everyone thinks it's a new bladder. I'm gonna be good as new, but there's issues with it, right? It's a piece of vowel that's not wired to our brain. So there's different ways of doing, you know, dealing with that, too. So I think, and I don't think I do a better job now than I did. Maybe when I was younger, of seeing patients and longer term and what managing their expectations, that is, robotic surgery like this pretty widespread. It looks to me like maneuvering those little arms probably takes a lot of experience and training. Uh, yeah, it's it's increasingly widespread for prostate cancer for bladder cancer. I think of multi port, which is the classic robotics. I think the statistics are about 20% of cases are done that way, which I think is probably an overestimate. That's what the robotic company tells you. So they're going to tell you everyone's doing it. But so I think it's probably on the upper end and there's nothing wrong with him again. An open approach to you know it's there's some short term benefits. The single port is something that is very unique and very new. You know that we're doing here, I think, here at UCSF, and like I said, I don't think still, we started at last year. There's anybody in the state that's that's doing it. Yeah, it's great to have your expertise and to hear about it. And I are overall succession today. Learning about how to treat glioblastoma is advances in radiation therapy. And then this really remarkable robotic approach to surgery for the bladder is, I think, really great, and, uh, also just highlight some of the exciting work that's going on at UCSF. So great for me to learn about, because I'm generally totally surrounded by breast cancer. So this is a great And, um, I want to thank everybody for attending and also the CMI information you'll get if you signed up for CMI. Uh, and then there will be a recording of this as well that will be posted. So I don't know, Christian, if you're on there, sometimes there's a link that they need and then do keep in mind we have our part to the best of the year. That will be in April. As I noted, as I noted earlier, and then I'll turn this over to Laura just for last closing remark. Well, I just want to say thank you to all of our Panelists. Those were great talks. And again I learned something from everybody as well, including Dr Proof. Even though I'm a urologist. So So thank you very much. And we do look forward to seeing everybody again in April. Take care. And good night, everyone