 Okay, welcome back. We still have people kind of filtering in, but I think we'll get started with the afternoon session. So, the afternoon session turns this over to the surgeons, and we talked a lot about metastatic disease and systemic therapy, but now Dr. Angie Smith is a urologist at the University of North Carolina, and may actually talk about not surgery. What I asked her to talk about was one of the questions that we got in the morning, was how do you decide when you should do surgery or when you should just watch, and it's a very topical and highly debated question in our tumor boards, and I think we'll hear, you know, how some of these decisions get made. So, Angie. Well, thanks for inviting me to talk today. So, really, it's about the small renal mass, and I'm going to just start out by just defining what I mean by that, because a lot of people talk about the small renal mass, but what does that really mean, and then talk a little bit about the management strategies that we can apply to it, mainly surveillance versus surgery, and then talk a little bit about decision-making, as she said. So, I figured we'd start with a case presentation to sort of put a patient to the sort of the whole decision-making process. So, this is a patient I had, 60-year-old male, who presented to the ER, and he had some lower back pain, and this is actually a really common scenario, we find. He came with another problem, and then the ER obtained a CT scan, even though his problem was actually lower back pain, it was just some muscle strain. He was ultimately diagnosed also with this small renal mass, which was discovered, which is 1.6 centimeters, and so this is often how these present, and so the question is what's his diagnosis and what are his options, and I'm going to use this case to kind of circle back at the end to talk a little bit about putting this in perspective. So, to start, what is a small renal mass? Well, it's defined as a renal tumor less than four centimeters, and in the United States I think it's hard to understand what a centimeter is, even myself, and so I put a roller up here just to put it in perspective, so forgive me if that's too simple, but for me, I just think of it as like a little over an inch and a half for a four centimeter tumor, and then, and sometimes it's defined as less than six centimeters depending on where you read, but generally it's four centimeters. It's asymptomatic, meaning there really are no symptoms that go along with it, generally speaking. It's confined to the kidney, so it hasn't spread, and then in terms of imaging qualities, we look at whether it's solid appearing, and then we call enhancing with IV contrast. What that means is it's bright with IV contrast, and so those are the things we're looking for, and that was the characteristic of this gentleman's tumor. So, a little background about small renal masses, well, over time the number of small renal tumors has increased, and as you can see from 1997 to 2006, there's been this increase, and that's due in part because we're imaging more in the ER, we do CTs and MRIs on many people, and I bet number, if not almost all of us here has had some kind of imaging for something, and so we call that an incidental finding whenever we find something that's not really related to why you got the imaging in the first place. And you can see this actually separates out the graph based on stage, and these small renal masses are by definition stage one, and you can see that top line going up, let's see, this top line is on the incline, and that really is responsible for that increase in renal masses. And so what we know is that in the 1970s, this is really only 10% that were found on CT or MRI imaging, and now it's almost half of patients with low stage are found this way, and the issue is the greatest incident is actually in older folks in over 70, and in the autopsy series where they actually looked at patients after they died for other causes before widespread imaging was in play, nearly three-quarters of the renal cell masses were clinically in apparent, meaning that the majority of them, that wasn't the cause of death, and so that supports the thought that maybe these renal cancers grow slowly. And so that represents a dilemma for us because if we're having these small renal masses in their older patients and perhaps these patients, the risk for surgery or treatment is a little bit higher in these patients, so can we safely observe some of these tumors? And then if so, what are the characteristics that define the tumors that can be observed and potentially undergo delayed intervention or no intervention at all? And then finally, what criteria might guide our decision between treatment and observation? So this is just a schematic. These are generally the three categories of management options for small renal masses. So first is active surveillance, and I'll talk a little bit about what that means. It's also known as watchful waiting if you've heard of that term. The second is ablative therapy. I'm not going to really talk about that today, but that's cryotherapy and radiofrequency ablation. What that means is cryotherapy is freezing the tumor, and then radiofrequency ablation is putting a probe in the tumor and basically heating it to destroy the tissue. And these are newer therapies, so the longer term outcomes are a little less known, so I'm not going to talk about that so much today. The third option is surgery, and that's partial or radical nephrectomy, and I'll talk a little bit about that as well. I have a little X over radical nephrectomy. Not to say that that's not an appropriate therapy for some people with small real masses, but generally speaking, that's pretty aggressive, so we try to steer away from that if we can, and I'll talk a little bit more about that later as well. So starting with active surveillance, what is it? Well, this is an approach that involves really no intervention at all other than the close follow-up of the patient, mainly with clinic visits, history and physical exam, laboratory studies, and imaging, whether it be CT, MRI, and in some cases ultrasound for some patients. And despite the earlier detection of these renal masses, there's not been a clear improvement in cancer-specific survival, so that suggests to us that maybe treatment of some of these tumors may not be necessary, and we know that up to 20 to 30% of these very small renal masses actually will be benign, so we don't want to overtreat when we don't need to be. So what's the issue here? Well, the problem is that not all renal tumors behave the same, and it's really difficult to tell which one is going to have malignant potential and which ones are benign. We do have biopsies to aid our decision-making process, but a negative biopsy doesn't necessarily mean that it's not a renal cell carcinoma. Also, CT, MRI, and imaging can actually understage renal cell carcinoma. So who is active surveillance for? Well, it's reserved mainly for patients who have a limited life expectancy due to other competing medical conditions, and patients where surgery is not an option, and where the intervention has a significant chance of decreasing quality of life. Now that's not to say that's all it's for. I mean, there are younger patients that are very appropriate for this, and really what I really stress to my patient is this is a shared decision that's not just the surgeon who's making this decision, it's very important that the patient weighs in as well, so it's really a shared decision-making process. So this is just a general scheme, but certainly there are many other patients who this would be appropriate for as well. So how do we decide when to treat, or if to treat? Well, we don't have a lot, we have biopsy, and that can be helpful, but there's also the growth rate, and I think that's really the mainstay of how we decide what we do. So there is a study that looked at over 200 patients who had an average follow-up of two and a half years, and they took a look at the growth rate. The average growth rate overall was about 0.28 centimeters per year, which is small, and that was smaller than the average growth rate for RCC-proven masses, which is 0.4 centimeters per year, and so we generally like to think that if there is an increased growth rate, that's going to sort of push us toward an actual intervention. The other thing that was helpful to know in this study is that only three of those 234 patients had metastatic disease, and on all three ended up having some kind of growth, so there were no reports of metastatic disease without some renal mass growth, and that's actually comforting to know since we use that as part of our decision-making process. But does no growth mean no cancer? And the answer is unfortunately no. This is a smaller study looking at two groups, one group had no growth, one had growth, and you can see that the renal cell carcinoma on pathology in that last row is not that different, so we really don't have a perfect method, but we do use growth rate to sort of guide what we do know in biopsy as well. So what's the follow-up schedule if you're placed on active surveillance? So the first thing I'll say is that compliance is mandatory, so again, you want to have a patient who's going to come back because it's important to keep monitoring this, so if I have a patient who I don't think or it's gonna be very difficult for them to come back to see me, I may not recommend active surveillance for that patient. Again, percutaneous biopsy can be considered in the American Neurological Association guidelines. They mention the role of biopsy in that way, and they also recommend that there's a CT or MRI or imaging of some sort at six months and then annually thereafter, and that's pretty conservative. We actually do a little bit more of an aggressive surveillance regimen at UNC, so in the first year we'll image every three to four months, and the reason we do that is because you really want to have a growth trajectory. You want to have two points on that line so you can see you're here or you're here, and that kind of gives you an idea of where we're going with the surveillance. And then if there's stable size in that first year, we'll move that out to every six months and then beyond that to annually. And then if there was a biopsy proven renal cell, and so we know that we're following renal cell carcinoma versus just a small renal mass, then it's recommended to get an annual chest x-ray just to look if there's any spread of disease. And then I have this last question, what's the trigger to treat? And it's intentionally, there's no answer there because there really is no gold standard on exactly when to treat, but I think that it's again a shared decision between the patient and the surgeon. And I also think that it really comes down to growth rate and then a lot about what the risks are for the patient for treatment, how sick they are, and so forth. So that moves into surgery, so when we do treat. And I know many of you know this, if not all, but I'm gonna just say this one more time and kind of go through what a radical nephrectomy is and what a partial nephrectomy is for those who are not aware. So radical nephrectomy is removing the entire kidney and a partial nephrectomy is just removing the kidney mass, leaving the rest of the kidney, the normal kidney behind. So this is just a schematic, but it's pretty simple. There are three main steps. The first step is to find the renal artery in vein. And then we use either a stapler or some kind of clips or just suture to divide the blood vessels. And then the second step is to divide the ureter, basically the tube that runs from the kidney down to the bladder. And then finally removing the remaining attachments of the kidney and the entire kidney is removed. For a partial nephrectomy, like I said, it was just removing the actual kidney tumor. And so it's similar steps, but obviously a little bit different here because instead of dividing the renal vessels here, we identify and then we put clips on them or bulldogs that are actually gonna be removed at the end of the case. We clip it to make sure the blood supply is not such that we're gonna have a lot of bleeding when we cut the tumor out. And that's the second step, is removing that tumor and just kind of cutting out that area and then finally sewing that defect together and then removing the clips at the end. So I just wanna talk a little bit about the rationale for partial nephrectomy. You remember at the beginning, I had that X around radical nephrectomy again. Radical nephrectomy can be appropriate in many scenarios, but partial nephrectomy, the rationale for doing partial nephrectomy over radical, stems from a couple different things. So the first study that I wanna talk about is just the fact that they looked at chronic kidney disease, so renal function that's diminished and that was an independent risk factor for death, cardiovascular events like heart attack, stroke, and then hospitalization as well. And so they did another study that looked at patient's survival for those who had small renal masses in both radical and partial nephrectomy. And the top line here is partial nephrectomy and they had better survival than those with radical nephrectomy. And the basis for that may result from a greater decrease in the renal function after radical nephrectomy. And oh, this is up for debate, but this is at least what we think about why we push partial nephrectomy over radical nephrectomy. There's also been shown to be an improved quality of life after partial. There's been shown to be equivalent cancer-free survival in patients who had partial versus radical for these small renal masses. And then I just wanna remind you up to 30% of these renal masses under four centimeters or benign. So again, we may be taking out a whole kidney for a benign lesion. So despite all of these factors that I mentioned, it's still fairly underutilized for renal masses that are small. And you can see this chart. So the black line, the black bars here are radical nephrectomy and these lightly shaded bars are partial. You can see that that's been increasing from the late 1980s up to the early 2000. It continues to increase currently. But the potential reasons for that underutilization is that there's a belief that maybe patients aren't really at risk for chronic kidney disease if they already have a normal kidney function or if they have a normal kidney on the other side. There's also a question of lack of comfort of the surgeon in performing the partial nephrectomy because there was, previously, there was a lot of people who were very comfortable with the radical nephrectomy using, I'm sorry, using small incisions for that. And doing that for a partial nephrectomy was more technically challenging. But now there's more use of the robot, and I'll talk about that just in a moment. And that has allowed a lot of surgeons who perhaps couldn't do that with pure laparoscopy to do it with a different type of technology and still have good outcomes and still have small incisions for the patients. And so as I mentioned, the robotic partial wasn't really described until 2004 and now we're seeing much more utilization of that since 2008 and I think that's gonna just continue to increase. So just a little word about what the robot is, and I say this because this is a really common question I get from patients in the clinic because they think that an actual robot is doing the surgery and that's not the case. So it's actually the surgeon who is really at this console that's away from the patient that's making the robot move. So it really isn't automated in any way. There's a surgeon involved. In fact, there are two surgeons involved. The surgeon who's at the console and then an assistant surgeon who's next to the patient sort of in his background over here and this person actually puts the instruments in all of these arms and also assists the console surgeon. And it's important to remember that the surgeon's hands are placed in these special devices so their actual fingers are actually making all of the movements themselves and performing the procedure. And this is what it looks like on the patient's belly. So just a few small incisions whereas it used to be for an open procedure if it was, it would be a very large incision and they would have a longer stay in the hospital, be a longer recovery time. So this has made a big impact for a lot of the patients with small renal masses who require treatment. So these are just a couple pictures from the OR just to kind of give you an idea of what it looks like. So this is just normal kidney, it's gonna be flat but these small renal masses will show up as just sort of little mound and you can usually tell and if you can't we can actually put an ultrasound in to identify the tumor. So we identify it and like I said we have already identified our renal vessels our artery and vein and we're gonna put a clamp on it so that we reduce flow just temporarily so we don't get a lot of blood loss. And then we take scissors and we cut around the tumor. It almost looks like an acorn once you remove it because it's almost like a little cone that you're cutting out right here. So this is the base of the tumor and they're cutting down and he's gonna cut all the way around this tumor and then remove it. Once you're done you get this divot right here in the kidney so this is all healthy kidney and once you have that you're going to take really just a fancy needle and thread to sew it back together and that's the final part of the procedure. So at UNC you can even see this take off of partial nephrectomy. This is for tumors that were less than seven centimeters. So these are small renal tumors some but some of them are larger and you can see that over the years these partials are really overtaking radical nephrectomy which is in the light blue. And then it's even more dramatic when you look at these true small renal masses that are less than four centimeters and you can see this kind of dramatic uptick in partial nephrectomy. So how does the follow-up schedule differ from active surveillance and that's something to think about in terms of how often you wanna be seen and the AUA guidelines again they recommend even though this is again there's not a lot of evidence that's behind all of this is sort of just expert guidelines. They recommend a baseline imaging within three to 12 months after surgery and that's just to take a look at how things look sort of at the baseline. So you have something to compare in the future if anything is worrisome. If you underwent a radical nephrectomy additional imaging is actually optional in these small renal masses and so you could potentially be done with imaging at least from the kidney standpoint at that point. If you had a partial nephrectomy the additional imaging is recommended annually every year for about three years and in some cases you may wanna extend that and then for all patients a yearly chest x-ray for three years to evaluate for any spread of disease based on the AUA guidelines. And again this comes from the AUA as well this is their decision-making algorithm I kind of it's a little more complicated than this but I think this is really the gist of what they're getting at and they categorize patients into four categories. So we have healthy patients here and here and we have sick patients. And we all have very small masses which are the masses less than four centimeters and then small masses which are this four to six centimeter category. And you can see that really the gold standard yes is surgery and when I say surgery partial nephrectomy is truly gold standard but radical nephrectomy in some cases especially if the tumors in a location where a partial nephrectomy is not able to be performed. But you can see that it's also recommended when patients are sick. So you can see it here either surveillance surgery because this is a slightly larger mass surveillance or ablation which I didn't talk about today but cryo or radiofrequency ablation for the very small mass in a sick patient. So but it's still an option and that's what I was mentioning. It's still an option for anybody with these very small or small renal masses and that's something to consider and again it's about the decision making process between the patient and the surgeon. So I wanna circle back to that first case presentation and sort of put it in perspective because this patient sort of did both and so as a 60 year old male again with the 1.6 centimeter renal mass and he opted for active surveillance which I think was appropriate. He actually had some comorbidities. He had had a stroke and he had some other medical issues so I think active surveillance was very appropriate for him. And so we decided to do imaging every three months just to start to kind of get that trajectory and to understand the growth rate of the kidney tumor. And so what we found was that it was a stable size at the three month but at six month we found a jump in the size and you can see there's that first image and then here it looks what it looks like at six months and the whole point is to capture this before it becomes something bigger but yet not over treat those who really didn't require treatment to begin with. So we made the decision together to go ahead and pursue robotic partial nephrectomy and so that was performed and the path confirmed renal cell carcinoma it still was stage one T1A because it was very small and we pour the guidelines obtained of follow up scan about three months later and you can actually see a little bit where the defect was no tumor anymore but that's generally the appearance that we find after for the baseline follow up scan. And so what we're gonna do with him is annual imaging for three years because we did a partial nephrectomy and that'll include not just a CT but also a chest x-ray and so far he's been doing very well. So just my summary slide I wanna just, these are the key points here. I think small renal masses are being detected with increasing frequency. We're gonna see more and more of these as time goes on and as we do more and more imaging in the ER. There's no reliable way yet to know which tumors are going to behave aggressively and so active surveillance and some ablative therapies like cryo and radio frequency ablation are options for the carefully selected patient or the high risk surgical patient but partial nephrectomy still is the gold standard and we have to remember that when we're counseling our patients. Now with the advent of the robotic partial nephrectomy it's become easier on the patient to have this surgery and that's an important point. Not saying that it's an easy procedure to go through but it certainly it can be easier than the open partial and that's saying something right there. But I think that our hope is that improvements in both biopsy techniques and imaging techniques and even just molecularly characterizing the tumor itself will help us to better characterize not just in general these tumors but really individualize it for each patient and that's really the hope. Once we have that it'll be even easier to figure out who would be best served with active surveillance so with that I'd like to thank you for your time and if there are any questions be happy to answer them. Yeah. That's another surgical talk. I think the nephrectomy is something that this crowd is very familiar with but specifically after nephrectomy this is Dr. Rampershout who's one of our colleagues at Duke Hospital. Well thanks for having me. Is there anybody in the room that hasn't had surgery yet? Anybody that's had surgery that's needing another surgery? I'm not selling myself I'm. I'm simply asking because I think a lot about recovery after surgery has to do with what you were expecting before surgery and the conversations that you had and learning about what it is that you have before surgery. I mean the way this ends up happening is oftentimes a patient will find out that they have a tumor and they'll show up and they will have done their due diligence and reading a whole bunch of stuff before they get to you and in their mind they have it what I need and really what has to happen is need to look at the patient look at the tumor and figure out what's gonna hurt you worse. Is the surgery gonna hurt you worse or is the treatment gonna hurt you worse than the tumor? That's kind of what Dr. Smith was talking about before. Sometimes you don't need treatment right away. Sometimes you don't need treatment at all and sometimes obviously you do and that kind of is where we lead into recovery. Expectations of recovery. Recovery is multifactorial. They're the tumor factors that help dictate the surgery you have or maybe don't need and then the you factors which are described by your functional status, your mobility, your general health, your nutritional status, motivation and expectations. Realizing that maybe the most important factors about recovering from the surgery don't have to do really with the surgery itself. Maybe they have to do with getting up and about realizing that healing is more about moving in healing rather than sitting still in healing. And also the emotional readiness for what it is that you have and what it is that you're getting ready to go through because largely this is hitting people like a brick wall. It causes me to examine my own life and realize that I can't simply plan for when I'm 65. I tell my parents now, save your money but don't save all of it. Because a lot of times you're just not ready to hear that this is what's happened and it's a process of learning about the disease, meeting other people that have it, meeting other people that have had successes and understanding what the future holds. Well, that color didn't come up. This is a Mac 2 PC process but really what this was pointing to, that was worse. These were tumor factors. So location of the tumor, the size of the tumor, whether it's localized or metastatic. Those factors are gonna help determine what it is that one would need if anything at all and how extensive that treatment is gonna be from the very beginning in terms of evaluation on through months and years later. There's the surgery factors. Is it gonna be an open operation? Are we gonna, is it so big and encompassing the big blood vessels of your body that we have to put you on cardiopulmonary bypass? We're gonna do it laparoscopically, robotically and the complications that are associated with it. And what I tell patients about this is I liken it to a hobby of mine which is driving cars. I've driven a little race car for over 10 years now at this racetrack up in Virginia called Virginia International Raceway. And most of the weekends that I go up there, there are a lot of hobbyists like myself that are there just for the weekend. We have other jobs. And we just like to get the speed out of us on a racetrack in a pseudo-controlled situation. And then there are other folks that are there that are training to be race car drivers and there are people that actually are racers and they end up being teachers at these camps that we go to. And it's pretty easy to realize, you realize early on that you could take the true racers and put them in cars that are half the car that your car is and they'll beat you around a track. It doesn't so much have to do with the car. At some point it does, but it doesn't so much have to do with the car as much as it does the driver. And really what you need to do is you need to find persons with whom you develop good relationships and that you feel confident with and you move forward with them. And not worry so much about, are they driving the robot car? Are they driving the lap car? Are they driving the open car? They feel comfortable with your caregivers. And then there are the you factors such as your general health, your performance status. Performance status and general health kind of go together. It's more about how functional are you? How active are you? These things are gonna play largely into your recovery because we're gonna need you or you by virtue of being here realize that you were needed to walk a lot. I mean your surgeon was probably driving you nuts asking you how many times you walked. Your nutritional status, your exercise tolerance. And later on we'll get into hopefulness. But exercise tolerance is one that plays in more commonly here in North Carolina. I did my fellowship at UCLA and I like to claim that and I was telling folks at the table today that I rarely operated on somebody less than more than 220 pounds in LA. And in North Carolina I operate on lots of folks that are over 220 pounds and often times your prehabilitation if you have an opportunity to prehab affects your recovery after surgery. So if you can learn to develop some exercise tolerance walking a couple miles a day every day. Anecdotally we know that this patient we feel that those patients do better. There are the tumor factors. And Dr. Smith spoke about this. Not every two centimeter mass is the same. You could have a two centimeter mass in a 90 year old that may or may not have a lot of comorbidities but they're 90 and they won. They won the game of life quite honestly. And that two centimeter mass was generally more than 90% of the time found by accident and isn't hurting them. But I know that I could. And so maybe we don't need to risk it by intervening and that's where active surveillance comes in. And again that's a shared decision. And you have the two centimeter exophytic mass in the 45 year old and you have to balance what's the risk of me or any treatment versus the risk of that tumor over time. And largely for 45 year olds we're gonna wanna intervene because there's a long surveillance period associated with it if you don't. And oftentimes when you treat a small renal mass in a 45 year old patient they do extremely well and that's the end of that conversation. You could have a two centimeter mass that's endophytic meaning entirely within the kidney or largely within the kidney. That's in the only kidney that the patient has and they're 45 years old. In that case you're gonna be wanting to make every effort you can to preserve the function of that kidney while removing the tumor. That's again different from the two centimeter entirely within the kidney but a non-functional kidney and a patient that has two kidneys that's 45 years old. That operation's different than this one. This is a partial nephrectomy almost mandatory. This is likely a radical nephrectomy that's probably most certainly less complicated than this. That patient will oftentimes have lower likelihood of complications and maybe even recover faster. Oftentimes this patient's going home the next day. You could have a 20 centimeter mass foot long in a 45 year old and that operation's completely different from any of these other ones that we've talked about and that recovery's gonna be different. And you could have the patient that has the thrombus that's entering the big veins in their body and maybe tracking all the way up to their heart. Even more complexity. So different operations yield different recovery processes. You don't need to go to medical school to see that there's something here that probably isn't supposed to be there. And then here you have this small renal mass. So the treatment for these two tumors is gonna be largely different and the recovery is going to be concurrently different. Some of it has to do with incisions and again this is where I get back to getting the driver working with the driver and not the car. Maybe it's appropriate if you need a robotic partial nephrectomy. I say that I did a fellowship in surgical oncology, not a fellowship in knife. If we need three one centimeter incisions to take your tumor out, we're gonna do that. If we need one two foot incision to take the tumor out, that's what we're gonna do. So yes, robotic partial nephrectomies are preferred for small renal masses when appropriate and when feasible and recovery is definitely different than if you have a large incision. You could do a pure lap nephrectomy where we make small incisions. When we're trying to remove the entire kidney and we extract the tumor generally from a fan and steel or low abdominal incision. You could have a hand assisted lap nephrectomy where you have a couple small incisions and then one to get the tumor out up here where you also place your hand to help assist you in the dissection process. Maybe the tumor is larger or maybe the patient has had a lot of intraperitoneal surgeries or maybe the patient has had dialysis and this is a non-functional kidney that has a tumor in it and once you've had dialysis or a lot of operations in the past your inside your belly within the sac that contains your intestines, there is a lot of scar tissue and perhaps you wanna stay out of that so you perform a radical nephrectomy through an incision and then you could have a big tumor like we were talking about before where we're gonna make an incision all the way essentially from your armpit across to the midline and all the way down to your pubic bone and it ends up being like a Pillsbury Dough Can where you pop the thing and it goes and that's what we do to you but that was what was required. So then what's the typical recovery? Typical, everyone's different. It may be five days for me and maybe three days for someone else. For a robotic partial nephrectomy, a lot of times the majority of the time the patient's in the hospital for one to three days. We tell them light duty for two to three weeks, resume regular duty probably at about four weeks and I use this terminology forget when do you start to forget and the reason I say that is because you could be sitting there having forgotten that four weeks ago you had surgery but you turned to pick up this glass and all of a sudden you're reminded because you're still healing and you pull on your belly and you feel it. So for open partial nephrectomies which are generally for the more complicated partial nephrectomies, the patients in the hospital for about two to four days we tell them to stay on light duty at about four to six weeks. After six weeks, before six weeks we ask them not to lift anything more than 10 pounds and after six weeks we tell them they could swing a golf club or do whatever it is that they were trying to do before. Another thing that I tell them is that God or whoever it is that you're believing in is going to tell you what you can and can't do if it hurts, don't do it and eventually that should hopefully go away and you tend to start forgetting at about three months. For a pure lap, laparoscopic nephrectomy where we're just, we're gonna put the small ports in, we're gonna remove the kidney. Usually you're just in the hospital overnight. You resume light duty in two to three weeks and you resume regular duty at about four weeks. A hand assisted laparoscopic nephrectomy is about the same just a little longer. Big open nephrectomy depends, depends on what happened and what was required. Spend up to a week in the hospital four to six weeks before returning to work, three to four months before you forget. It can be more depending on what was involved in the operation. So all of that we tell patients and we've been telling patients that for a hundred years, not that we've been doing all of these operations for a hundred years, but just that, I mean this whole six week thing, no lifting greater than 10 pounds for six weeks. We've been saying because the person that taught us told us to say that and the person that taught them told them to say that and a hundred years you can go back 115 years. And that's what we've been saying. And that doesn't really matter as much as one factor that's impossible to measure. It's amazing how hopefulness is disproportionately important when it comes to recovery. Patients that I could put the biggest operation down on people and the majority of what I do is kidney cancer, do these huge operations in patients and they oftentimes will be very hopeful, hopefully because of what things like Dr. Harrison and I have talked to them about, but they do well. No idea why that is. We call it the placebo effect and a lot of things that we do, but it's really hopefulness and the belief that you're gonna do well, those patients do well. The patients that think that they're not gonna do well or overly pessimistic, dark, that I'm trying to get out of the darkness before we go into surgery, and I'm not talking about that day, I'm talking about days and weeks beforehand, something's gonna go wrong. So hopefulness, there's this intangible quality of hopefulness that we can't describe, we can't measure, and all we can do is try to inject in the conversations that we have with patients. We've all, that treat kidney cancer, we've all seen the patients that should have done not so great that have just flown and years and years and years and years later. We've seen all the home runs that we've had and a lot of it has to do with reasons that we can't explain yet, but maybe we'll never be able to explain them, maybe that's the part that the patient brings by virtue of their personality and their support system and the experiences that they've had in their lives, maybe the faith that they have. So I think that's an important part of recovery that we don't talk about a lot and the reason we don't talk about it is because there isn't a survey for it and there isn't a lab for it. If you have any other questions about anything, I heard a couple of people talking about their conditions and where they stand in their disease process and if you ever have any questions and you just want some off the cuff advice or conversation, you can always get in touch with me. That's it. Thank you very much for that really thoughtful discussion of how we recover from this and I think that's a nice segue. We're gonna go back toward medical oncology again. The transition point is at least at UNC and I think a lot of different places, the nurse navigators who help you navigate. When do you call the surgeon? When do you call the oncologist? When do you call the radiation oncologist? How do you do this? What do you do? Who would ask questions? This is who you call. So. Thank you. Hi everyone. So I'm Sarah Kulmeyer. I'm one of three nurse navigators with UNC's Zerologic Oncology Program. I'm also an oncology certified nurse practitioner. So nurse navigators really help navigate help navigate your journey, help you get through where you're trying to go. We help make sure our team provides the best communication. We help you communicate with your providers and with your team. I kind of like to think that we help connect the dots between everybody. Generally nurse navigators are really experienced nurses. They've been nurses for a long time. They generally have a high degree. UNC's cancer hospital navigators are all certified in oncology. Then a little bit of history on navigators. In the 1980s, I think there was some kind of recognition of the need to help orchestrate a patient's cancer journey. And in the 2000s, we started to make it a standard of care. So how is your nurse navigator multidisciplinary? Which is something that is a big focus that UNC is making sure we have a good multidisciplinary team. Your navigators are gonna help guide you through initial talking about initial testing, treatments, appointments, diagnosis and helping to educate you along the way and answer any questions that you might have. Your nurse navigator is gonna help you be your advocate and your liaison about providing support, identifying support and making sure that you get in touch with the right support to help any need you may have. We do serve as educators as well about everything along your journey. So we're gonna educate you about your diagnosis. We're gonna educate you about your treatment options. And we might even help provide education when treatment is needing to be changed. This kind of is a really cool picture I found about how the navigator kind of brings everybody together. So you can see here. So you've got nurses, pharmacy, nutrition, genetics, rehab, survivorship, psychosocial issues. And then here it kind of cut off a little bit. But you have your oncologists, your surgeons, your radiation doctors and your pharmaceutical folks. So the navigator is really kind of in the middle here and we're your orchestrator to make sure that you can reach all these people whenever you need to and that we can help get you to the right spot. So then your nurse navigator is really kind of your direct link between the patient, yourselves, your survivors and your team. We're probably the easiest people to get a hold of on your team and can make sure to get you in touch with the person you're trying to reach. Especially when it comes to the urology clinic at UNC. So yeah, generally most nurse navigator programs, your navigator is kind of your one person to contact for all your needs, whether it's a nursing question or changing an appointment or a question about a treatment or an upcoming visit that you might have. So nurse navigators are also gonna be meeting with you through your journey, talking to you about different issues you might be having and help to really break down the barriers and care that you're coming across. Because that barrier might be different for every patient. You might have a financial barrier, you might have a transportation barrier or you might have just need some support. Nurse navigators are really great about knowing where the local resources are. So we're gonna definitely make sure that we get you into the right programs and the right groups that you need. Like I said, kind of bringing down those barriers, whether it's transportation, financial. We do a lot of at UNC getting people lodging. We know that our patients are traveling from really far away. So we help to find them places to stay while they're coming for their visits. And connecting you to providers outside of UNC too. We work a lot with Duke. We work a lot with other facilities. Our patients are coming from really far away. And so we might work as a team with some of their local doctors. Having a navigator is a really great person where those outside people can call us and we can help facilitate anything that's needed. So education, I know Deanna is one of our navigators who's here with us too. With UNC Urology, we're really trying to bring education into our navigator program and making sure that we educate our patients about anything that they need along the way. So from initial diagnosis of their malignancy to their treatment or to even just nutrition, exercise programs, things like that. So local resource education and support. Yeah, we're just trying to get you to the right people in the right spot. So the urology team at UNC. My name is Sarah Deanna's here. Melissa Holt can be with us today. We're all certified in oncology about a little more than 20 years experience between the three of us, providing nursing care for you guys, so thank you. That's fantastic. You may seem really, really easy, but it's not. So our next talk is Dr. Mike Harrison. We're now in the last couple of talks really gonna look at the future. We talked a little bit about the new drugs in second line therapy, but really where the new stuff is is some stuff in imaging, which Mike over at Duke has been doing a lot with in the last several years, and then after that we'll be talking about immunotherapy. So, here you go. You need to load up your phone right now, yeah? That's for pregnant. It's an AKCA, it's an AKCA, pet and nurses. All right. So thanks, Kim, for having me here and the organizers. So I'm gonna talk over the next probably 20 minutes or hopefully less about pet, which I know there's a lot of excitement about. So I'm gonna talk a little bit about what is pet, and I'm gonna try not to get too technical, but I think, again, there are a lot of misconceptions about what is pet and what it can do, how it works, things like that, so I do wanna just mention a little bit of science behind it. I will talk about what could pet tell us, so what's the promise of pet, and then I'll give a few examples and kind of review the evidence hopefully pretty concisely. So this is a nice slide showing kind of the evolution of technology over the past over 40 years, and you can see from left to right in terms of CT and pet both, the resolution has gotten a lot better over the years, and then it's only really the last maybe 10 or 15 years where it's gotten to the point where we can start to be able to use it for different purposes. So what are the potential advantages of pet CT over just say CT alone or other imaging, and I think the advantages are really that it marries both structure and function, so structure is in terms of the CT having a very high spatial resolution, being able to look at different types of tissues, bone, fat, air, other things like that, and then the pet on top of that adds the function so we can characterize lesions, how are they say taking up sugar or doing other types of things depending on what kind of tracer you're using, and then that may allow you to better detect lesions or at least to maybe better separate out which lesions are lesions to be worried about and which lesions you should not be worried about. So this is a nice slide kind of showing that marriage, so on the top row you have a pet scan and it's black and white, you'll notice you have a CT in the middle row, and these are different views, kind of a frontal view, a side view, and then the last column is a patient lying on his or her back with their belly button pointing towards the ceiling. And as you can see at the bottom, the pet CT marriage, so they first take the pet scan and they colorize it, and then they overlay the CT on top and that gives a lot more information than just one or another alone and then they can kind of play with the different features back and forth. So on the topic of pet being kind of a functional type of an imaging, what types of things are unique to cancer, how does cancer function different from normal cells? And so this is a classic slide first published by Hannah Hannon Weinberg in 2000, I believe, that's now been updated in 2011, and these are showing some kind of cardinal features of cancer or hallmarks of cancer biology. So these are things like deregulating cellular energetics, so that means cancer takes up glucose more than normal tissues, things like evading gross suppressors, other things inducing angiogenesis, which we all know is very important in kidney cancer, and then sustaining proliferative signaling, and of course avoiding immune destruction, which is being increasingly recognized now as important in kidney cancer. So since I think especially FDG-PET is so misconstrued, I do wanna just talk about a few basic principles, and so to do that I'll have to talk about a little science, but also to note, when most people say pet, they don't say FDG-PET, they don't say sodium fluoride pet or some other kind of pet, they just say pet, and usually what they mean is FDG-PET, which is basically looking at sugar and how the tumor takes up sugar. And so this is a kind of a cartoon that has a lot of science in it, but basically you can break this down very simply. What it amounts to is what you're looking at is a cell membrane, so I would say a cancer cell. There are glucose transporters in that cell membrane, so sugar flows from a gradient into the cell, and what's unique to cancer cells is the cancer cell is relatively inefficient, so it doesn't go towards that bottom pathway that's in the mitochondrion, it just kinda cycles back and forth, and so in doing so it takes up a lot of sugar relative to normal cells, and we could take advantage of that with FDG-PET imaging. So this is a slide showing FDG, so kind of a sugar-like substance flowing through the same sugar transporter that sugar would. And normally sugar, these arrows here, see if I can point them out, these arrows here are showing different kind of enzymes that convert the sugar into all different types of things, but the cell can't get rid of the FDG, so it can't flow back out, it also can't flow down into other pathways, so that FDG is then trapped, and we can take advantage of that to do imaging, and so what we see is this FDG that's trapped in cells. This is where it gets a little bit complicated, because you can imagine if a patient has one or several tumors in their body, what are you really looking at? Are you looking at all of the tumors? How do you kind of quantify that? And so what is commonly used is an SUV Max, it's called, and that's, again, I'm sorry to have to mention these kind of technical terms, but that is one voxel, and a voxel's like a pixel, so a pixel is two-dimensional, it's a square of voxel is three-dimensional, it's a cube, and so it's the cube in the tumor that has the brightest intensity. So what you're doing then is you're boiling this whole tumor down to one little point that's the very brightest spot, and that's the most common measurement called SUV Max. There are other ways of looking at this, so one of my colleagues at Wisconsin likes to say, images are just more than one number, in fact, they're very complex, the data that comes out of these PET scans is just enormous, and so one of the reasons why we use SUV Max is it's very nice, you have one point that you boil everything down to, but the disadvantage of that is you don't really capture all of the features of this lesion, so think about this lesion, it may have spots that are brighter than others, it may have different nests of cells that are behaving differently, some are good, some are bad for other, lack of a better way to kind of explain it, so there have been other ways of kind of quantifying and describing what you get when you get a PET scan, so one of those is SUV Peek, where you actually take some diameter around the brightest voxel, so the SUV Max, so like one centimeter around and you quantify that, you can also quantify the whole thing in terms of the total brightness, say, and you can do measurements, so this is a list of just all kinds of possibilities, just showing that SUV Max is what is commonly used and if you're an oncologist or other doctor were to get a PET scan, chances are what would be in the report is an SUV Max, it would say this is something that looks like a tumor here and this is its SUV Max, it's seven or whatever it is, for now these other measurements are being looked at for research purposes, but aren't really a standard of care, but as bioinformatics gets better and things like that, I think that the field of PET research may move to looking at some of these other things because they may be more important and may not, I guess for lack of a better way of putting it, may better describe the tumor burden in the patient's body than just boiling each tumor down to one little point. So if you look up in NCCN guidelines or you look in different guidelines and recommendations, Medicare's recommendations, for example, they do not routinely mention the use of PET scans in kidney cancer and so these are some of the reasons why most PET tracers including FDG are eliminated by the kidney, so you have what you can see is the FDG kind of flowing down the track from the kidney into the bladder and so on and so forth out the body. Also early investigations seem to indicate that primary kidney tumors, so tumors within the kidney had relatively low sugar uptake so it didn't seem to be kind of useful there. So FDG PET didn't really seem to add a lot to just conventional CT imaging, for example, for looking at renal masses. When they kept looking at it, it looked like FDG PET performed a little bit better for detection of distant metastases so it was fairly specific meaning that if it was a positive FDG PET you could kind of believe that result. So in the next part of the talk I'm gonna talk a little bit about what FDG PET could tell us and I'm gonna argue a lot of this is still a work in progress but I think there's a lot of hope as the technology advances and maybe new tracers are used, we could have some real use from PET. So the first area where I think PET may be useful is better characterization of small renal masses so basically differentiating malignant from benign small renal masses. I'm sorry, I missed Dr. Smith's talk, did she talk about gerontuximab or? Okay, all right, so I'll talk a little bit about what's maybe the most promising tracer gerontuximab. The second area where I think PET could maybe tell us something useful is we know that there are patients at high risk of recurrence and we know that because of different features when Dr. Ampersad takes him to surgery when he looks in the pathology may make them more likely to recur so if they're T3, T4, if they have other high grade those kinds of things, what we think those patients are probably more likely to recur but we can't see the disease on our conventional imaging so maybe we could see that better on PET and then the key is if we see it hopefully we can also treat it and have good tools to treat it to improve outcomes for patients and so I think it's important to note both of those things have to be true. And then the third thing which is something that's near and dear to my heart is in patients with metastatic kidney cancer can we improve prognostication or prediction so prognosticating how long patients may live which is important for a lot of things but also predicting when therapies might work or even just treatment monitoring are treatments working or not. Current prognostication systems as I imagine was discussed this morning rely really on clinical factors so things like laboratory values, the patient's performance status but maybe PET should be in there and I'll show you a little bit of the data around that. The other problem is that standard radiographic methods so CT are a little bit problematic in kidney cancer without getting into it too much there are some situations where we see that the tumor is growing on CT scans and so conventional research methods of measuring the tumors might say this patient is progressing when in fact the tumors are changing in their characteristics of taking up different IV contrast and we think no maybe they're dying in the middle or something like that. And there are other scenarios where we can't really evaluate patients so for example a patient who has tumors only in the bone tumors in the bone are very hard to measure and hard to quantify so maybe that's a situation where PET could be useful over CT or say bone scan. So without further ado I'll get into the first one of these which is characterization of small renal masses and this is I think one of the most exciting uses of PET so this is gerontuximab so CG250 which is labeled with iodine so this is a monoclonal antibody so an antibody that recognize what's called carbonic and hydrase nine on the cell membrane of specifically clear cell kidney cancer so keeping in mind there are other histologies or types or flavors of kidney cancer it's specific for clear cell kidney cancers and so keep in mind that in terms of interterminate renal masses if you think about it about half are clear cell renal cancer but then the other half are made up of some with limited malignant potential so things that we would worry less about papillary and chromophobe histologic types but also benign tumors oncocytoma so there is a concern for over treatment of small renal masses specifically some renal masses that are greater than or sorry less than or equal to four centimeters so we know that patients who have especially full nephrectomy or even partial nephrectomy are at risk for chronic kidney disease and then for cardiovascular disease so maybe we can differentiate amongst these different categories of interterminate renal masses with something like gerontuximab and so again I don't wanna bore you with too much biology but this is I think a nice cartoon just showing one of the pathways that's really central in kidney cancers and that's the von Hippel-Lindau tumor suppressor gene so what you can see on the left here is that in conditions where there's normal oxygen levels in the tissue the VHL von Hippel-Lindau tumor suppressor basically marks this thing called hip one alpha hypoxia inducible factor one alpha for degradation and it's degraded. Now in clear cell kidney cancer what happens is in a large majority of cases that VHL is inactivated for some reason maybe a mutation as a consequence it doesn't inactivate that hip one alpha that goes to the nucleus of the cell and sets off this whole signaling cascade where there's growth factor over expression of a lot of different things that Jeff which I imagine you all are familiar with but also carbonic anhydrase nine so this is something that's kind of specific for kidney cancer based on the biology of kidney cancer and specifically clear cell kidney cancer the most common type. So this was an important trial that came out relatively recently where they were looking at this compound so gerontuximab the antibody again against CA9 took about 200 patients with complete data sites all over the US and these were patients who were going to go to surgery for arenal mass and what they did is in these patients they did a PET CT with gerontuximab and then they also did a contrast enhanced CT and so what they were asking is is the PET CT better than the regular CT and their standard of truth then it was surgery so in these trials it's always important you have to have some kind of gold standard you're trying to say gerontuximab PET is better well what's the gold standard that you're looking against? So the sensitivity and specificity for clear cell kidney cancer was pretty good 86% so these mean kind of the confidence you can get for ruling in or out the diagnosis of clear cell kidney cancer positive and negative predictive value so again different ways of kind of looking at that were fairly good the criticisms were though that these patients were actually not just patients with small renal masses which is what I think this could be used most for only 52% so only about 100 of those had pretty small renal masses 20% had really large renal masses where they would have just got an effect to me as standard of care other things that are important to note and this is the case for a lot of PET compounds so I just mentioned this here all PET compounds are not the same they have different features they have different half-lifes as far as how long they last in the body they have different technical specifications so a scanner may be optimized for the most common type FTG but it may not do very well with this gerontuximab so there's really a trial needed in patients with small renal masses to kind of sort this out and patients who are gonna go not just patients who are candidates for surgery so I do wanna show you a few pictures because I think this is pretty neat so this is a sample image so thinking about what's the standard of truth or the gold standard the patient had a one centimeter mass it was clear cell kidney cancer on surgery and this is what it looked like on non-contrast CT this is what it looked like on the gerontuximab PET so it was positive this is what it looked like on a fusion so in this case both the contrast enhanced CT and the PET fusion would have picked this patient's this patient's kidney cancer up now contrast this with this scenario so this is a patient with a 1.8 centimeter oncocytoma so meaning a benign type of a tumor in the kidney at an effect to me so and my arrows I realize have moved here but you see the mass there in the kidney seen on a contrast enhanced CT and it would have been worrisome it was positive so worrisome based on contrast enhanced CT but on the PET CT it did not uptake the gerontuximab so this may have in this case may have saved the patient from surgery now in this case of course the patient did get surgery as the standard of truth but in clinical care this is a scenario where the gerontuximab might have been helpful so scenario two so what about surveilling patients who are high risk I'm not gonna go through the evidence because I think that a lot of it's retrospective and not a lot of it's not that great but I'll just sum it up by saying that a lot of different guidelines whether you wanna look at the NCCN the American Urologic Association the European Urologic Association basically say that the role of PET for follow-up of RCC remains to be determined and I think the main concern is false positives so if you do a PET scan maybe it picks up some lung nodules that weren't otherwise seen but maybe it makes you more worried about lung nodules that are nothing in the first place and that's the real concern I think there so I'm gonna move right into the third kind of area where I think PET may be useful and this is looking at response to therapy so specifically tyrosine kinase inhibitors so drugs like sutent, drugs like seraphonib and so these aren't meant to be read but just to show you there at least seven trials that were summarized in a nice review that came out earlier this year and what's key about these trials is each one of them had relatively few patients the largest number of patients had the largest trial that is had 44 patients and they ranged down to having 10 patients and if you look, most of the drugs studied either sutent or seraphonib sometimes a combination they had different timing most of them were looking after one cycle of sutent so usually about six weeks but others looked at different time points and they did use mostly SUV max but some used some other features as well in other words these were a little bit heterogeneous small trials, different designs so sometimes when that's the case it's hard to draw firm conclusions so I'm just gonna show you the very largest trial and just kinda talk about the top line results so this was the one with 44 patients these were previously untreated patients who had metastatic clear cell kidney cancer treated with sutent and what they did is they did this FTG PET imaging at baseline they did an early time point at four weeks and they did a late time at 16 weeks and what they were really hoping to see is that responses at either four weeks so a change from baseline at four weeks or a change it from baseline at 16 weeks would correlate with either overall survival or with progression free survival and interestingly the response at four weeks did not correlate with any outcomes but on the other hand progression at 16 weeks did predict an inferior survival they also find a finding that's been found in other trials which is that a high SUV max at baseline so a lot of lighting up bright, very intensely and number of positive lesions predicted for inferior survival so I'm gonna try to show you some more pictures cause I think this makes it more interesting so what you see here is a patient who's kinda falls into that camp so a patient who at baseline had lesions and you can see the little arrowheads pointing out some different lesions the patient had a response after four weeks of therapy and then after 16 weeks of therapy had new lesions indicating progression and then this is just picking out one lesion on a cross-sectional imaging showing how it decreased in uptake from baseline to four weeks this slide isn't necessarily meant to be read but just showing you kind of the differences and things that were shown in the different trials so in some trials early assessment of response by FDG PET could predict both progression free survival and overall survival whereas in that largest trial it couldn't in one trial high baseline FDG PET uptake so being really bright at baseline seemed to indicate the disease was more aggressive and then the last one is Dr. Rathmell and colleagues trial so this was looking at patients interestingly prior to kidney surgery or removing the primary tumor and they did show that lower baseline uptake were more likely to respond to seraphanib which was an interesting finding that was in patients with clear cell kidney cancer not in the non-clear cell subtypes so in the next slide and one of the last slides I'm just gonna look toward the future and we can make a list of tens of hundreds of different PET tracers that have been looked at in cancer but these are a couple that I picked out that I think are interesting just because they may or may not be specific to kidney cancer so one if you remember back to that hallmarks of cancer diagram one thing that may be unique to kidney cancer is this tumor hypoxia effect and so they've looked at this compound that's usually abbreviated F myso or something else because it's unpronounceable and they showed that PFS but not overall survival was shorter in those who had more hypoxia meaning low oxygen levels in the tumor versus those who had higher oxygen levels this is another type of PET so looking at again if you remember back to that hallmarks of cancer diagram looking at tumor proliferation and this is the group that I worked with at the University of Wisconsin looking at basically a labeled thymidine so a compound that's used in DNA synthesis when cells are proliferating they're needing a lot of this compound as kind of the raw materials so they're turning over a lot of this and so what we showed in this study is that we could characterize or quantify changes during sous-tent exposure and during withdrawal and so if you keep in mind sous-tent is given on a four two schedule so it's given for four weeks on two weeks off we showed that VEGF is associated with that flare and in an exploratory analysis patients who had less clinical benefit appeared to have a large withdrawal flare and so I'll show you a little picture of that so this hopefully you're able to see but versus baseline this patient had a decrease in intensity in this particular lesion from here to here the patient had their plan two week holiday of sous-tent which is in the FDA approved package and the patient had a large withdrawal flare this patient did not do as well as patients who had less of a flare so just indicating that this may be a tool to sort out or tease out biology and see how each tumor is acting so in conclusion I would say that PET is very promising I think though there's a lot of work to be done during tuximab I think it is important and may eventually play a role in management of small renal masses FTG PET CT though really isn't a standard for surveillance after nephrectomy it may be in the future may be useful for evaluating response to targeted therapy so drugs like sous-tent, affinitor, so on and so forth but I think we're still a long way from qualifying it as an actual biomarker for response and lastly I'd say there's lots or more room for research, new tracers some of which I showed you and new methods to make things better for our patients and better help with management decisions so thanks for your attention and happy to take any questions So our last talk is Dr. Sergio Samoscos who's a non-collegeist at the University of North Carolina his specialty is immunotherapy and I can't tell you how many questions I've had already today about immunotherapy so that's why we saved it to last so you all had to stay all the way to the end of the conference and so tell us what's new thank you Kim for, it might be to give a talk about immunotherapy my role within the University of North Carolina is actually melanoma specialty so you would ask yourselves why melanoma doctor is trying to give a talk in renal cell and the answer is supposedly we are seeing the melanoma doctors are seeing us, melanoma doctors are seeing us doctors from the future for what is going on in the field of renal cell cancer which lacks approximately one to two years in development in relation to what is going on with renal cell carcinoma does anybody dare to say what this looks like? Patients wise, not doctors so I tried to find a picture in the internet about how a cancer cell looks like and how lymphocytes look like so I want the patients to understand there is a size difference between what's a cancer cell which is usually a big thing and how these tiny things are trying to go against the cancer cells and kill it so we have a size difference and sometimes number of cells of immune cells and function matters okay, so the talk point is that since it's Christmas I'm gonna give you a couple of books for recommendations books for Christmas it's I'm gonna try as simple as I can with respect to describing what is a normal immune system functioning because a lot of lessons from the normal immune system functioning you will answer yourselves about what are these drugs that are coming out in the renal cell carcinoma mean and how do they work so an important aspect of what is immune surveillance and immune editing so and then what are the mechanisms of cancer immune system suppression just to explain the variety of different mechanisms that exist and why immunotherapies is not one side fits all also would like these audience to remind the high dose bolus hyal 2 it is no longer a sexy drug as this has been out for 20 years but nevertheless should not be overlooked as progress goes by and then the future for now is immune checkpoint inhibitors and that's what we're gonna talk in the end and then the question is whether the future is for everyone so these are the books for Christmas the left side book I read when I was a resident 14, 15 years ago it is written very almost 15 years ago so there's not gonna be any excitement about the recent advances of immunotherapy but it's gonna give you a very nice history of immunology and immunotherapies in cancer you will see all this drama that has happened over the last 100 years about questions like that a scientist had does the immune system work or does not have a role so we had a lot of ups and downs throughout the 120 years as to whether the immune system plays a role so there's a nice book here pretty big like 300, 350 pages not an easy book to read but I would therefore recommend and the one I'm trying to finish when I'm going back and forth to work through an audiobook this is a generic history of cancer book there's no talk about a lot of immunotherapy but again you're gonna see how doctors and researchers are by all means human beings and they're having their own biases and how progress is are being made so the purpose is not to explain you how normal immune system works but show you that basically we don't talk about immune system in general we talk about two different arms of the immune system the one that is less relevant for cancer and the one that is more relevant for cancer so this is the adaptive immune system the immune system needs to remember what the cancer cell is because it's a non-self so it's not something non-specific and the key to all this the key is the interaction of these cells that are called adygs and presenting cells these are the cells that pick up stuff that is known for that is known for in from the environment this can be viruses this can be bacteria but yes it can be cancer cells cancer cells are non-self cells so these are sample from the micro environment and are being presented in these antigen presenting cells and it is this key interaction with this other cells that are called lymphocytes that you saw in the very first slide that is the key to educating the immune system so that's a different way of seeing the adaptive immune system fancy picture where antigen is where antigens are being picked up at these antigen presenting cells these are called dendritic cells from the Greek word dendros which means tree so they have these spiny projections and it's again an uninstructed naive T cell that is gonna come and encounter the antigen presenting cell and then it's gonna get activated and either it's gonna kill the cells or some of them are gonna be left behind for memory so that's a very simplistic approach of what is adaptive immunity and again the key interaction here is the interaction between the antigen presenting cell and the lymphocytes so here's your first kind of complex slide but the way I'm gonna present it is like it's basically the interaction between the antigen presenting cell that I showed you before and the lymphocyte, a T cell is actually so complex that over the last 20 years there have been so many molecules that have been identified to play a role in this interaction and it's no longer a simple interaction of a signal what means that these antigen presenting cells gonna present the antigen and oh, the immune cell is gonna get activated the decision, so it's no longer one what's called first signal it is a number of other things that the interaction between these two cells have to be taken into account and whatever is in red it means that these are actually proteins are gonna say no, I'm not gonna get activated and then those things that are green these are the cells that say yes, I'm gonna be activated so the net effect of whether an immune cell is gonna actually get activated is the net result of the positive and the negative factors and it's easy to understand that this looks to me like a complex car with multiple brakes and gas pedals so that's how complex nature is and right away you're beginning to see things that you may have seen already on the internet, you're seeing things like CTLA-4 so there's already a drug against CTLA-4 it has been used for renal cell cancer it's called Hervoid, it has not been approved yet also you see these other negative immune checkpoint protein that's called PD-1 or PD-C1 that is the target for nevolumab or pebroluzimab pebroluzimab that was FDA approved melanoma three months ago and then whatever you can see in red it means that there are already drugs in development so it is no longer just the PD-1 that you see or the CTLA-4 there are a bunch of actually targets that are currently in clinical development so this is a very hot area of interest so there's gonna be more to come over the next five to seven years okay so this is the gas platter scenario in normal states so if you have two gas pedals in one break then it's a go and that's a nice looking car that actually makes a turn and it does not go upside down and this usually happens when there is an early stages of an infection an immune system has to become activated very simplistic the way presented but this is a good way to understand how it goes and then when the immune system takes care of business in the normal states then all these several of these negative immune checkpoint proteins are being upregulated and then basically you have your car nicely parked ready to be used for something else so I want people to understand here that cancer and immune system there is constantly an interaction I remember I was a third year medical student in Greece when our pathologist said our body makes approximately 30,000 cancer cells per day and the only reason that we don't develop cancer is because we have a constantly working immune system so there is always this tendency the Darwinian tendency of our bodies to develop mutations to become something different to evolve over time but there is constantly the system that's called immune system that is trying to seal things off so therefore any conditions can turn a normal tissue into a cancerous tissue and by definition the cancerous tissue is slightly different from the normal tissue and that is perceived as foreign as a non-selfmade immune system and in so doing the immune system is trying to eradicate those cancer clones and then there is this constant interaction between how a cancer becomes genetically unstable develops new mutations becomes more different and how it actually tries to suppress the immune system and how this battle between the immune system and cancer is going on and on and that has been, and that probably has been going on for years and years to come this is not an overnight event and eventually cancers develop because the immune system has failed so when somebody has cancer it's basically a failed immune system so there's not anything to fix it it's not like if you increase your exercise or you increase your activity or you improve your diet or you get a supplement, it's gonna get better it is already broken and therefore there have to be ways to restore in the way of drugs I believe in alternative medicine but the effects of it are very well unknown in a patient with metastatic cancer so again, will the future be one size fits all? I just talked to you about one way that the immune system is suppressed and that is by upregulating these breaks but there are a number of things that are going on there are many different ways that the family can become dysfunctional I quote one of the very nice phrases that Alexander Tolstoy has wrote in Anna Karenina there's one way that the family can be functional people would be happy and you know kids love their parents and vice versa and everywhere is happy but there are many ways that the family can become dysfunctional that is how cancer is there are many different ways that your immune system can become suppressed so here we go so if the cancer cell does not upregulate these HLA molecules the ones that require for the first signal the immune system is not gonna see it and therefore that's how cancer cells evade the immune system that's one way to do it the other way to do it is to produce all these molecules that basically suppress not only those cells that are supposed to pick up these antigens and instruct those lymphocytes but suppress pretty much everything suppress the antigen presenting cells but suppress the immune cells as well and guess what many of these things that are being secreted by the cancer or when the lymphocytes coming in contact with the cancer it can be a toxic effect so as this nice review article from Tessa Whiteside who was my neighbor in neighbor office in Pittsburgh she says immune cells in the tumor microenvironment are functionally impaired and I'm adding and are killed so your lymphocytes are getting killed by the cancer cells and you all are patients and you understand how to read a complete blood count test but what I want to emphasize you here is I'm gonna show you eight different patients CBCs, simple as that the common with these patients is that all of them have metastatic cancer and the one thing that makes a big, big interest is that the fact that all of these lymphocytes are low so there is a fundamental problem in most of patients end-stage cancer that their lymphocytes are low in the blood so for people who don't know what is a high dose bolusal to it has been FDA approved therapy for 20 years, it's not for everybody it is a very toxic therapy, not everybody can do it it has been given in hospitalizations this is called a hospitalizations called the cycle two cycles include a course and we can evaluate things between every two courses so this is what IL-2 does so this is our very first patient that was treated at the University of North Carolina with renal cell cancer so what you can see here is that before he got into the treatment his lymphocytes were low and then when he started to get IL-2 his lymphocytes disappeared and that's what IL-2 does makes the lymphocytes disappear from the blood and they're going to different parts of the body including the cancer cells and they're supposed to eradicate the tumor and what happens is when the cycle ends then the patient shows up right before the next dose and his lymphocytes are almost double right before the second course so what I want to emphasize again do not forget drugs like IL-2 so IL-2 is otherwise called T-cell growth factor I call it the T-cell steroid if patients in the way of immune suppression is actually they just don't make a lot of immune cells IL-2 could be a very good drug to give so the same thing now but now I have this thing there which means that the cancer cell can actually immunosuppress because it can also develop properties of antigen presenting function and then all of a sudden you see that the lymphocyte can take instructions, wrong instructions from the cancer cell as you can see there are more breaks that the cancer cell can induce as opposed to gas pedals and this is now the scenarios when somebody has cancer, okay so you may have advanced cancer and your first signal is functioning and you have two breaks in one gas pedal and therefore you're looking like a formula one card that is on high breaks but if for example your immune system the cancer does not have expressing those things that makes the cancer cell visible then you're like a car that is driving in the middle of the night without knowing where things are and you can have the third situation of immunosuppression where things are functional but the cells are dying because the cancer is suppressing them and this is a car on fire so what the immune checkpoint inhibitors in the cell cancer and that seems to happen in 50% of patients with renal cell carcinoma is that you may actually be able with one of these drugs to eradicate one of the two gas pedals and that could be sufficient for the immune system to get activated and sometimes if you use two of them at the same time okay and this is the PD-1 plus the epilimum out then this immune system is really revved up to the point of going up in the air so this is a most updated list of clinical trials using these immune checkpoint inhibitors in various cancers and I want to show you the renal cell cancer in relation to other cancers so what I want to show you is that if you use these two drugs the epilimum and the nevolumab in various doses in combination you can rev up the immune system to such an extent that you can see response rates of as high as 44 now if you use only nevolumab in renal cell cancer then the responses are less but nevertheless much better for responses that you get in other cancers like lung cancer or variant cancer so what I want to emphasize is that different cancers would respond to these drugs in different percentages and it seems that the renal cell cancer behaves in terms of response rates similar to melanoma so again see where the epilimum and nevolumab was given in patients with lung cancer the responses was only 16% whether the benefits and challenges of these new classes of immunotherapies so definitely the way we see that in melanoma when epilimumab was approved in 2010 we were able to give immunotherapies in a much larger number of patients we were giving epilimum in a 90 year old we were giving epilimum in a 70 year old with congestive heart failure we were giving epilimum in somebody with coronary artery disease I also cannot be given in those patients so the application of immunotherapies will be much larger in a larger group of people the same way we saw that in melanoma what else would be convenient it's gonna be an outpatient therapy you don't have to be admitted for this horrible five day course of high dose bolusile too and in fact if you come to the MICU the medicine intensive care unit at UNC you're not even gonna have a bathroom so it is definitely less toxic okay so that's no questions asked but again we have to see the less toxicity in a different perspective the benefit of IL-2 is that you will do it for two months or four months or six months and then you're gonna be done with these kinds of immunistic point therapies potentially the side effects can be long lasting in particular if you use the combination of epilimum or any bolumab will they be more effective so we now mind we have linked response rates that I just show you with clinical benefit which is progression for your overall survival the trials are too early right now to say whether this high response rate would actually lead to longer survival but it's very safe to think this way but unless we do follow these trials over a longer period of time we will not be able to know the long term benefit and the challenge is we're talking about drugs that are it's $20,000 in infusion here so we should do better job we as doctors to really refine which patients actually are candidate for and I think I predicted that this combination of drugs can be effective in up to 50% of patients but definitely not 100% of patients and for how long we're gonna give these drugs so right now the drugs at least the approval of the Pabroluzma for melanoma is basically indefinite so as long as you have cancer and you respond to that then you're gonna be getting Pabroluzma forever is that the right thing to do I mean this provides a huge burden to the insurance companies and the healthcare system and again as I said as response rate correlated with longer benefit and what's the cost and how to combine these drugs with other drugs and I intentionally did not do that because I would wait for you to make your questions in the final discussion so my summary and conclusions is that future is for some but definitely more than the lucky aisle to candidates so you shouldn't be privileged because most of you will be candidates for both of these drugs the Pabroluzma Malone or in combination with Epilimumab but not one side fits all that I think I showed you that there are many ways that cancer either family can become dysfunctional and this is one of them and do not forget that there are also good old drugs so taros and kinase inhibitors can some of them I've seen that they have response rates 20, 30, 40% and people have been on that for years and years to come and there are also high dose bolusile too that you should not forget but if the patient is in an advanced stage of disease you just cannot beat up a dead horse with any immunotherapy in which case you have to use other types of treatments so these treatments are not for everybody so I thank the six, seven patients and their families who have trusted us to give them high dose bolusile too in the hospital and I'm sure that they are eager to see something less toxic than IL-2 and the GG program that refers patients to us for this thank you Thanks all the doctors thanks for your lectures my father is 94 years old two and a half years before he found occasionally I found a small renal mass in the left kidney at 1.2 cm now it grows to the 2.5 cm still in the so-called active surveillance and during this time he had a stroke recovered pretty good for the stroke but after that he used some drugs to prevent the stroke and also majorly concerned stroke again so you use the plavix according to the insert one of the side factors of the plavix it will cause the Y-cell count to reduce if that may potentially cause immunoproblem for the kidney cancer this is the first one secondly one of the options it says it can do the partial nephronectomy but some doctors said because of his age and also even without ice cream or plavix it may cause difficult recovery so the partial cut may be more difficult to recover than the total cut is that true or not thank you I think Dr. Rampers I will let you answer the question I guess maybe I'll rephrase and you can tell me if this is correct one question is how does plavix affect decisions about going to surgery and then also how do you decide when you're going to go to surgery or not when there's these other factors yeah plavix causes the Y-cell count low will affect the immune response to the existing cancer or not we'll let Dr. Moscos take that one afterwards I would predict I'm not very confident about the plavix side effects and what types of Y-blocks have been affected if that affects the neutrophils which probably would be the case then these again are innate immunity cells that are not significantly playing a role in the overall cancer and recognition and everything so if plavix does affect non lymphocytes I would say that they will not affect the response to new therapies yeah and I would think that we would in that case in the patients with cardiovascular disease we would see disproportionate percentage of patients with immune modulated secondary malignancies so what was, can we go back to what those questions were one was the, how old is the patient, I'm sorry it's 94 years old two years before was no much complaint still no complaint about the mass in the kidney no urine, blood, nothing but it had a stroke between the two years so what you're describing is you're talking about a tumor that's incidentally diagnosed that isn't doing anything to them not yet not yet, but in a patient that has significant comorbidities including age not the least of it you really have to put things all together again like I said before and you determine what's more likely to hurt the patient is the treatment of the tumor more likely to hurt the patient or is the tumor more likely to hurt the patient in a situation like this, again without having met your relative and knowing them and their functional status and their other medical history and not knowing whether or not their parents lived to be 120 years older without knowing that there are very few people that are going to encourage an intervention at this time considering that the likelihood of hurting that patient with an intervention is higher than the tumor hurting them thanks and by the way, even with by size criteria and though that's growing let's say you're talking about a 4 cm sporadic tumor that is kidney cancer let's just make those assumptions the likelihood of, I mean what you're worried about is you're worried about that spreading so first of all it's going to it's growing reasonably slowly and the likelihood of that spreading is somewhere between 1 and 3% per year so even that is still low, right? Do we have another question? I just wanted to ask Dr. Harrison a question and maybe the answer is nobody's looked but now that all the immunotherapies are coming around has anybody looked at PET scans or novel imaging in maybe Dr. Moscos can comment too Yeah, so he may be more of an expert on that than me but I know that people are interested in that in imaging PD-1 I don't know if it's possible So that falls into how to decrease the cost and find patients who most likely respond to the therapy so there are some promising tracers so it's a little bit complicated so I told you that there is a number of mechanisms of immunosuppression one of which has to do with the enzyme it's called indolamin the oxygenase it is an enzyme that basically metabolizes an amino acid that's called tryptophan so there are some tracers that we are actually interested at UNC to use actually called C11AMT which is an analog of tryptophan that we hope that patients who have immunosuppression they would have high levels of the tryptophan analog and we would plan to design a trial where we would image them before treatment and then give the PD-1 and see whether we can correlate activity of the tracer with with a response to therapy but nevertheless the community yet I think and again that's my bias the communities there are so many of these that we have to there are so many options and right now there has not been a commitment towards one but it seems that AMT is more likely to move forward I think so many cancer therapies are partly immunosuppressive and the tyrosine kinase inhibitors of course they have off-target effects that could be partially immunosuppressive as well so if you put that in the context of the immunotherapy approaches where you treat blocking the PD-1 pathway you get responses in about half the patients on a good day like you said is there a correlation between the response rate to the initial therapy the specific tyrosine kinase panels and target affiliations with the response to the PD-1 could you use that as a predictor you're asking me I'm asking anyone yep maybe I can I can take that so again with the caveat that I'm not an immunologist I know that you know different companies are developing PD-1 inhibitors and PD-L1 inhibitors and they seem to have their own assay for looking at PD-1 positivity so you know in the trials PD-1 positivity doesn't perfectly predict response and then also patients that are PD-1 or PD-L1 negative also seem to respond so I think and you can correct me if I'm wrong but there's a lot of nuances as whether they're looking at tumor cells or other cells and what they're using is the cutoff and I was told there was I believe as AACR there's a whole session about this at some recent meeting about just how kind of messed up that the whole assays are for lack of a better way of putting it. Was that the question or not? My question is you've got two competing influences you've got the anti-tumor immune response and that's what you'd like to get you also have direct anti-tumor effect by a compound or a drug so if you treat with the compound that is going to target the cancer cell for many of those treatments you're also going to be targeting the immune response so if the immune response is playing an important role in eliminating the tumor cell you're actually working against yourself often but that's going to depend very much on the target profile of an individual candidate drug so I guess my question is when you list these 10 or so various targeted therapies that are being used in renal cell carcinoma they're all going to have different kindnesses that they had they're all going to have different effects so do those effects do they have a predictive value towards the response to anti-PD1? So the effects of the kindnesses? If you have a patient that doesn't respond to a particular tarrison kindness inhibitor are there kindness inhibitors that don't work but then that would then predict a response to PD1 because they don't work and part of the reason they don't work is because they didn't block the immune response the immune response was playing an important role to control the tumor so now you get rid of the break now the immune responses instead of suppressed so I'm not a kidney cancer specialist I can tell you that these paradigms of combining kindness inhibitors with immunotherapists have been done in melanoma and are ongoing in melanoma because we know that you may actually want to have benefit from both worlds so like a direct and that humor effect that actually may lessen the immunosuppression or whatever that's going on and then coming up sequentially with an immunotherapy there has not been any clear signal yet because these trials are ongoing nevertheless the combination of these drugs is very kind of toxic if you give them concurrently like there's a lot of hepatotoxicity I'm aware of a trial where Sutent was given a combination with Nevolma but it was very toxic but I have not heard of whether a response to a tyrosine kindness inhibitor would actually correlate with a response to a PD1 thank you any last questions one more sorry as my father the candidate for the potential active watching we're always concerned do we need to do biopsy to make sure that cancer or not as I understand for all the medical therapy always required pathology level diagnosis but surgery maybe not because anyway you can get the tumor then you can do that is that true or not one of the common statements by surgeons is that if you're going to take it out that was your biopsy right the fact of the matter is in your father even if you were to know what that was you're very likely not going to want to do anything about it considering the whole the whole view of things and biopsying it would just it might give you some more information but it's not going to affect what we currently do right now so there is it's not as though biopsy is completely without risk so why put somebody at risk if you're not going to act on the information that you're going to attain so so yeah so in a typical patient like you described typical right never met your dad we wouldn't encourage or I wouldn't encourage biopsy simply because it's not really going to change at least my opinion but then again it's a shared decision that's fair right we live in America and it's not he even told me that boy was beautiful good most older patients do you know one and we're talking about that 80 plus year old they've won the game of life largely and that's easy for a 40 year old to say but maybe when I'm 78 I'm going to be thinking you just have to finish but 94 year olds will commonly say why are we doing anything but I think you do one of the questions that so I think yeah so you kind of read my mind I was going to ask Ed to play devil's advocate what if jaren tuximab scans were approved would you do that so maybe reassure this gentleman you know maybe add more anxiety if it was positive yeah g250 from the land of the LA we you know in this particular case even if I knew you said it's two and a half centimeters uh... so on the basis of size historical pathologic studies on the basis of size there's an 80% slightly above that 80% chance that it's hidden chance we know that knowing it isn't going to really change what you might want to do um does that make sense if you were in a better total health situation um and you were trying to determine whether or not the risk of treatment were worth the intervention then maybe that would be appropriate I think this question kind of sums up the day like we have a lot of new therapies we have a lot of new advances and a lot of new things to do but ultimately it comes down to every decision right from the decision to do surgery to how to manage the drugs to how to choose which drugs and how to do all this is ultimately very personal so I hope that we've been able to give you a little bit more sense of what's out there and what goes into some of these decisions what it is we think about and talk about when we're trying to help guide you through this whole process so with that it is three o'clock I want to thank our speakers and shared their day with us voluntarily to try to help clarify this but also to thank you all for coming for being a very interactive group and for taking a really active role and interest in this disease kidney cancer I would encourage you to follow up with the kidney cancer association the these if you want to watch any of these again they'll all be online I would guess probably by Monday the kidney cancer association puts these meetings together around the year about quarterly and let us know if there are topics that you want to hear about there's way too many topics to cover today we tried to pick what seemed kind of relevant new and fresh and burning but if there are good topics you want to hear let Mike know, let me know let the people of the KCA know and next time we do this we'll cover those topics as well and we're here all the time and safe travels