 Okay, good morning, it's nice to see familiar faces again. This is, how many years have we done this, this is like our, eight or nine, eight or ninth annual national patient meeting. Those of you who don't know me, my name is Chris Wood from the Urology Department here at MD Anderson Cancer Center. This is Kari Konoski from the Kidney Cancer Association, and we're here to welcome you to MD Anderson and to our national patient meeting. So in the past we've done this several different ways, a couple of years ago it was all didactic lectures and I remember looking out on the audience in the afternoon and people's eyes were sort of glazed over. So we decided to mix it up and last year we had all case presentations which went over very well, but again people sort of said they wanted to have some form of didactic as well. So this year we have a combination, so we'll see how that goes. For any housekeeping issues that you have, please see the conference staff members at the registration table, they'll be happy to assist you. Our conference today will be producing a live YouTube broadcast as well as videotaping for a webcast to be posted on the Kidney Cancer Association website at a later date. As we are streaming live video during our question and discussion sessions I'd like to ask you to not identify yourself or any patients you may reference during your questions presented to the panel members. There will be no facial recognition caught by the cameras of the audience only audio. Please be certain you fill out the authorization for use and disclosure of protected health information form and return to the registration desk. Please silence all electronic devices during the duration of the day and if you need to place any phone calls please step outside the conference room to avoid taping interruptions. And just as an aside we'd like to thank the supporters of the conference which include Pfizer as well as Genentech. So we'll go ahead and get started. I'd like to remind the speakers to please be on time and we'll start off with Dr. Serena Matin for the Department of Urology speaking about the management of small renal masses. Thanks Chris. Good morning y'all. So I'll go through in the next 20 minutes, hopefully a little bit less over the really revolution that's occurred in our field which has really been very exciting. Even about 14 years ago we really only had two treatment options to offer and of those two we really were not keen on offering partial removal of the kidney because we were concerned that maybe it wasn't as good of a cancer operation and most of what we did was open removal of entire kidneys even for small tumors. But things have changed a lot and we've learned a lot over the past several years and now while I don't have really the time to go over all of the information for you what I'd like to do is give you a summary of where we stand now with some of these options. So they range from things such as active surveillance which is completely noninvasive probably the most kidney sparing option there is to ablative therapies to partial removal by either open or robotic means and robotic just being a way of doing it laparoscopically and of course there's still complete removal which we can do either open or laparoscopically I won't really talk about this but I'll kind of start from here and then work our way through this series of options that are now available so the question you might be asking is why do we want to go about saving kidneys and the first concern really is one of a cancer one and as it turns out for tumors less than four centimeters and probably for some up to even seven centimeters the cancer outcomes are the same it really makes no difference in terms of recurrence whether you take out part of the kidney where the tumor is or take out the whole thing the other fact is that there's a pretty good chance that there that it may be a benign tumor we're looking at as many of you know some of you may not but scans really do not tell us if a tumor in the kidneys benign or malignant in most cases not without getting some tissue and while we've learned for example is that women in the 40 age 40 40th decade are twice as likely to have a benign diagnosis so we were taking out all these kidneys for a long period of time to find a small benign tumor and we really didn't help that patient more importantly however in relation to taking out entire kidneys when we don't need to is this what we're learning about development of chronic kidney disease and what we mean by kid disease is not the cancer but basically the kidney is not functioning well and as it turns out there's this interplay between our hearts and our kidneys if the heart doesn't function well the kidneys don't function well and if the kidney is in functioning well the heart may not function so well so one can accelerate the other when they're diseased and by taking out kidneys unnecessarily those those conditions can be worsened globally for the whole patient these are some of the largest studies done in terms of just kidney disease and what I want to highlight for you is this part of the graph that the purple and the green here so age is down here and the percent of patients with chronic kidney disease and one thing you can see is that as we get older our risk of chronic kidney disease goes up pretty quickly in some cases and especially if you add high blood pressure diabetes very common conditions these days then that loss is actually even accelerated gender doesn't really make a difference ethnicity doesn't make too much of a difference and so now if we can combine those two and we're just starting to be able to do that a little bit this is one of our colleagues at fox chase cancer center and what they did was they took a large population based database and looked at the comorbidity and this charlson scores the way for us to measure how sick a patient is basically a zero is they're not very sick one or two means they have one or two medical conditions that are significant high blood pressure heart disease for example diabetes or three or more and then here's the size of their kidney tumor the blue areas indicate the likelihood of death from any other cause but kidney cancer and the red indicates the likelihood of death from kidney cancer and you don't really have to be in medicine to see that there's a lot of blue and so particularly when we look at the small renal tumors in those with high comorbidities you can see that this red part is a fraction of their risk of the entire risk of death now obviously the ratio changes as the tumors get bigger and also for those who are much healthier so we have to think about that and one of the things that we talk about when we're trying to you know when we're wringing our hands trying to decide what what's the best option for a patient is is this concept of competing risks on one hand you have the tumor that's growing we worry about it becoming incurable metastasizing and we also worry about it to a lesser degree but to some whether it's going to continue to grow and destroy the kidney and losing function that way and on the other hand you have the comorbidities the medical conditions that the patient carries and that bring a baseline risk to the patient which we cannot change much in terms of if we have to perform surgery and changing those risks of surgery those patients may be a risk of dying from those medical conditions like the graph I just showed you and we may not alter that by removing something in their kidney and also every time we touch the kidney whether we burn it cut it whatever it's going to lose some function so these are the some of the competing risks that we have to consider so that's just to kind of give you some baseline as we go about these options so for a lot of these reasons and the other one that have essentially left out but fairly important is that what we've learned is that when tumors are small particularly less than three centimeters the likelihood of metastasis developing is exceedingly low they also tend to grow very slowly now most of that information comes from the older population and so we just have to be a little bit careful translating that to the younger population but in general that's a pattern that we see displayed and I'm going to show you some of that information a little bit later but again putting all that information together what we've now have learned over many years and long follow-up on many many patients is that partial removal really is the gold standard for small tumors and even long-term it's got 98 efficacy okay so it's an excellent option and we can do it open or robotically laparoscopically doing it laparoscopically is basically we're doing the same operation but we can do it less invasively so this is an somewhat older slide that shows all the different techniques we can use to remove part of the kidney these days we don't even take out this much normal kidney we cut it much closer to the tumor because we've also learned that size of the margin doesn't really make much difference so I'll show you a couple of examples this is a patient I treated many years ago a poorly functioning left kidney for reasons we don't understand why you can see this right kidney is very big it's compensated for the other one not working well but there's also a big tumor right where all the vessels come into the kidney and so obviously this is their solitary functioning kidney and the question was what could we do with this can we preserve the kidney and this is where open partial nephrectomy has a great role and we can do very precise dissection here's the tumor here's the margin here is the ureter the tube carrying urine down and a lot of the blood vessels which we've already divided and that's what the tumor removed and we could do all this with the blood vessels clamp so that it doesn't bleed because the kidney gets a tremendous amount of blood from the heart and as it turns out that tumor was benign so imagine if someone had decided to remove that kidney and that patient was on dialysis so and the kidney function was unchanged actually so here's another case just to take it to another extreme of a 47 year old with a three and a half centimeter mass that was highly suspicious for renal cell carcinoma this is considered by most to be not preservable if you look at the scans very carefully sometimes you realize that it can be as long as you follow very precise anatomic boundaries so what I have here in blue is showing you the outlines of the tumor inside the kidney the yellow highlights where the urine is collecting which is where the contrast is concentrated now here's another view tumor surrounded by the urinary collecting system and this view shows the tumor with the arterial and venous anatomy so fairly complex resection this is what the kidney looks like this is part of the tumor bulging through the fat that's inside the kidney we've done an ultrasound so we can see inside really well during the ultrasound and see exactly where we want to resect and this is where we start that very fine dissection we've clamped the kidney now you notice it looks pale compared to up here we've clamped that it's actually under ice and then what we can do with very precise dissection is remove the entire tumor with essentially minimal to no margin in this case here we see blood vessels that we've tied off and then after the kidney reperfuses nice and pink not bleeding functioning very well and this is a classic renal cell carcinoma that was removed with negative margins this is the CT scan six years later of that kidney no recurrence okay so some of these cases we can do robotically and robotic again is a way of trying to do it laparoscopically I used to do laparoscopic partial removal very difficult to do and physically quite honestly fairly exhausting so this allows us to do it in a bit more easy fashion for the surgeon I think it's probably a somewhat of a better operation and that we can use do that suturing of those fine structures much more quickly and much more precisely and for those of you who aren't familiar basically it's it's two parts there's the surgeon console so the surgeon is sitting slightly away from the patient there's an assistant by the bedside and this is what does the work this is the actual robot but the surgeon basically is looking in these binoculars that gives him or her a 3d view and by putting the fingers in these master controls can manipulate the tips of the instruments attacks to this machine so just to kind of give you an idea of a fairly straightforward partial removal here what we're doing is clamping the artery to the to the left kidney here's the vein we're going to put a clamp on that this instrument right here is controlled by my assistant everything else that you see is controlled by the surgeon sitting at the console now here what I've done is left the fat on top of the tumor you don't even really see the tumor this is the fat that normally covers the kidney we've left it on top of the tumor we've stripped it off the rest of the kidney I've already marked out where I want to cut and now we're going to start cutting exactly in that area and because there's no bleeding every time I cut I can make sure that I have normal tissue on both sides and this is the foundation of this operation is being able to ensure that we remove the entire tumor in a bloodless field so I'm going to look at it make sure it looks good that looks great and now what we've done though is cut across a bunch of blood vessels and we're going to suture them so this is the assistance suction but these instruments and also the camera are controlled by the surgeon sitting at the console and this type of suturing is what is fairly difficult to do laparoscopically at least in terms of at least doing many and doing it quickly and with experience we've we found that we can even approach very difficult tumors what we call the hyalur tumors like the other one I showed you that we did open several years ago but ones that are in very difficult locations and all of these we've been able to do robotically with the technique that we call micro dissection and being able to preserve preserve the kidneys here's another example of these actually I'm going to stop it just to show you here's the tumor in the upper part of the left kidney and this is the vein to the kidney so the tumor is right below it here's an artery going up to immediately adjacent to the tumor and then the tumors here and immediately adjacent to where the urine is collecting inside the kidney now this video is sped up twice as fast so that it was minimally edited so I apologize if it looks like it's all super fast it's not but basically what we have here here's that vein the branch of this vein that's going up to the tumor the tumor is covered by the fat here and by basically dividing these we can continue to separate the tumor and at the same time start cutting off the blood supply to it once we've done enough of that what we'll then do is again put a clamp on the artery sometimes on the vein also and then the rest of it we'll just cut the rest of it by going through the rest of the parts of the normal kidney so again that's a big vein that we just went through this is all normal kidney some of the fat back there so minimal blood loss two-day hospitalization fairly aggressive tumor actually a type two papillary the patient's done well at about a year and a half out here's another example just to show you something slightly different also left side hyalur tumor we're going to do that dissection go through these areas as much as we can and then at some point we'll encounter some bleeding stop what we're doing stop the clamp the blood supply and do the rest of it with the blood supply clamped but right now there's good profusion of the kidney as we do all this let's just speed it up a little bit here we go we're going to clamp the artery and resect the rest of it the confidence in being able to know where to cut a lot of times is based on that ultrasound that we do I haven't showed you so that encompasses the options of a partial removal the other option we have is a blade of therapy we were really hot on this long time ago not so much anymore I'll tell you why in a minute the idea with ablation is that you're going to use energy to kill the tumor and not really do surgery to remove anything basically every six type of energy has been tried electrical sound lights lights and can photodynamic therapy radiation therapy really the two that are established and used are cryo ablation colt or radio frequency ablation which creates heat so cryo ablation is the oldest that's been around essentially freezes the tumor and the surrounding normal margin and we can do the do that percutaneously right through the skin under CT scan or do it laparoscopically and we can monitor the treatment really well actually so here's a case showing a tumor in the left kidney one month after cryo ablation what we see is there's no perfusion at all all the white stuff is where blood is flowing there's no blood flowing to it but it looks bigger but that's because we treat a margin of tissue around it and there's also some swelling and at three and six months you see continued shrinkage of the area radio frequency ablation uses heat electricity that generates radio frequencies and they heat the water in a particular geometry determined by the type of probe that's used and here's some various ones here's an example showing a percutaneous treatment patient under CT scan has that treated and again we follow it with scans over time looks bigger at one month but there's no blood supply to it and then it shrinks over time now the downside with these as I mentioned is that they don't appear to be quite as good as surgery so I showed you with partial removal it's about 98% or better at greater than five years at less than five years these are about 88 to 90% efficacy okay so not bad but not as good a surgery and so what that means is that we reserve it for very specific types of populations patients who are elderly high surgical risk because really we do see very few complications with it we do see some complications but really very few and not major ones so it's reserved for that type of population and there's also it's um I talk to my patients it's a little bit like having a ball and chain a little bit because we have to do a biopsy beforehand otherwise we'll never know what it was we do have to do all the imaging at our center because it gets to be a little bit complicated if we try to do it elsewhere and then sometimes we have to do a blaze biopsies afterward because we found out that the scans aren't perfect at being able to tell us with confidence whether there's residual cancer or not as it turns out so with surgery to remove a partial kidney you don't really need to have all that intensity of follow-up now I want to spend a couple of minutes talking about biopsy because there's always concerns and questions that comes up with that there's you may read still on the internet and still even some textbooks about the the results not being always reliable that's actually changed a lot of with modern techniques and with the but people who do the biopsy the interventional radiologist working much more closely with the pathologists so we can actually get fairly reliable results in most cases these days the other criticism of this is that it may not change the plan and that's true but actually now that we have more reliable results sometimes it does change the plan I'll show you an example of that complication rate is very low there is a bleeding risk but it's if it happens it's usually minor severe ones are really rare one of the questions we get asked all the time is that we're going to spread cancer by putting a needle in it this doesn't really seem to happen again because of the modern techniques that are employed it adds cost there's no question it's a procedure and it's about half a day to a day of your life so in terms of these days why do we do a biopsy the traditionally and to this day we do it whenever we're concerned that there's another cancer they may have spread to the kidney fairly uncommon dr. wood actually has done some really nice work showing when we should be considering that and there's also cases where lymphoma can occur so there's no question about doing it in those cases but anytime we're not removing the tumor I recommend a biopsy when we do active surveillance ablation or as I mentioned after ablation or whenever we think there's a suspicion of a benign mass and maybe that'll change the plan I'll give you an example of that here's a 76 year old patient multiple medical comorbidities Charleston score of four so fairly severe kidney function is terrible it's not really a percent but we could think of it as a percent if you want to when you get to 15 you get to to the risk of hemodialysis basically and that's just comes from heart disease and vascular disease and this patient has a three centimeter renal mass so it's not a size we're completely comfortable watching over a period of time so lots of competing risks here here's this MRI showing the tumor I recommended a biopsy it's done under MRI metal doesn't show under MRI so you see a shadow and as it but as it turns out the biopsy showed on oncocytoma completely benign tumor there's really no risk of this spreading and becoming curable and what we decided to do was just surveillance so that we don't unnecessarily risk the patient's life with intervention that's not going to change changes life so that brings us to this concept of active surveillance for my last couple of slides um bottom line is that the majority of tumors under surveillance that are three less than three centimeters in the elderly population grow very little this is what's called a waterfall graft graft and what it shows here is the change in tumor size over 30 months some tumors shrink most of them stay completely unchanged and some grow but very minimally there's a few that act mischievously and those are the ones we need to watch for and that's why we need to keep doing scans on these and we can't just tell patients to forget about it and there's other multiple studies over probably thousand now that show that overall it's a very slow growth rate in most of these so to summarize a lot of the data that I haven't really shown you just because a tumor grows doesn't tell you that it's cancer actually a lot of the benign ones can grow the risk of metastatic disease is very low as I mentioned people worry about losing an opportunity for intervention and that doesn't seem to be the case because it's usually they grow slowly enough that we can catch it and still do kidney sparing procedures and it's a reasonable option for those who are elderly as I mentioned before so to summarize you know all of these options what they've brought us to today is the ability to really individualize patient care to a level and degree that we really weren't able to do that before and a lot of this also applies actually to patients with metastatic disease we don't really have time to get into that except maybe during the panel discussion thank you all okay thanks Serena our next speaker is Dr. Jose Karam from the Department of Urology who will be speaking to us about management of locally advanced kidney cancer good morning I would like to thank Chris and the kidney cancer association for the opportunity to be here today and to present this topic on the management of locally advanced kidney cancer so this is in a way the other spectrum that Dr. Mateen just presented the first talk was in small masses this one will be on larger tumors and more advanced disease so just to define advanced kidney cancer one way to define it is if you have a direct invasion of the cancer into the inferior vena cava that's the big vein that drains blood and goes back into the heart and kidney cancer in about 10% of the patient likes to go there the other disease entity is invasion from the kidney itself into nearby organs such as the adrenal gland the colon the pancreas or others and this is considered to be stage four disease another entity is a spread of the kidney cancer to lymph nodes around the actual kidney and this is still considered stage three and finally local recurrence which means the kidney has been removed either partially or completely and then disease recurred in that same geographical area so I'm going to start first by talking about invasion into the vein either the vein of the kidney called the renal vein or the big vein called the inferior vena cava and this is one way to classify it and this is described by the Mayo Clinic as you could see here level one is gone from the kidney into the renal vein and barely into the vena cava level two has gone into the vena cava but still below the liver level three is above the veins of the liver but still not in the heart and level four is gone already into the heart and this is by direct extension as you could see here and as I just mentioned this entity of a tumor thrombus which is a tumor inside the vein occurs in up to 10 percent of patients with kidney cancer and aggressive and complete resection are very important and can provide cure and up to 70 percent of patients especially if there is no signs of spread or metastasis outside of the abdominal area this is our experience here over a period of about 16 years about 600 patients with invasions into the vein the median age or the average age about 60 years with a follow-up of about two years tumors tend to be large about 10 centimeters on average and most of them are clear cell tumors which is the most common type of kidney cancer as you could see here most of the tumor into the vein is limited to the renal vein the next would be going into the vena cava but still below the heart and the minority thankfully is gone into the heart the these surgeries are big surgeries the average blood loss is almost a liter the surgical time on average is about three hours hospital stay is about a week so this is not a simple operation and definitely not a simple recovery for our patients complications in the first 30 days could be as high as 25 percent and I'll go more into the details of complications later and as far as survival if there is no spread of cancer elsewhere the average survival is about five years and again these are all averages all the numbers I'm giving and if there is spread into lymph nodes or elsewhere into distant areas such as lung or bone or liver the average survival is about 15 months and these are what we call predictors of survival so this helps us try to identify what patients might benefit from surgery or might live longer depends on some factors such as if you have the clear cell type there is a higher chance of surviving after surgery if you have a high grade which is a grade four or sarcomatoid or invasion into the fat of the kidney or spread into the lymph nodes the chance of survival becomes less compared compared to if you don't have any of these typically this is a big operation we do them through large incisions either sideway incision or up and down incision and it doesn't really make much difference it depends on the surgeon preference at that point this is our experience with more advanced tumor thrombus this has gone into the vena cava or the heart again the average age as you could see here about 60 years hospitals stay about a week and the average follow-up is about two years and you could see there is a large number of complications that could happen after these surgeries about half of them are considered to be minor complications the other half are considered to be major complications the complications that occur in the first month after surgery are mostly related to lung function for example if the patient's not breathing deep enough they could have um you know a telexosis or what is considered to be compression of the lungs the lungs aren't opening enough to supply good oxygen or pneumonias or problems with the kidney function or problems with intestines such as inability to go to the bathroom and these are things that keep the patients longer in the hospital these are complications that happen after 30 days so typically at this point the patients are at home most of these complications are minor but there are some major complications as well so the most common one is chronic kidney disease which makes sense because the patient now has one kidney so that is one of the side effects of these kinds of surgeries again the predictors of complications are mostly age is the more significant one so the older the patient the higher the chance of a complication happening after surgery and in some patients there's also a risk of dying after surgery it's a small percentage but it's a something that we discussed with the patients before undergoing such a procedure because it's very important for the patient and the family to understand that there is some risk involved with these kinds of surgeries when the invasion is quite deep into the big vein and going into the heart as well this is the second topic as far as the advanced disease the first one was tumor going into the vein this one is tumor going into adjacent organs this is a CAT scan that you see here of the tumor in the upper portion of the right kidney and it has invaded directly into the liver this is not a spread you know through the blood into the liver this is a direct extension of the liver and this is the patient that had this operation and this is done in conjunction with one of our colleagues from the liver surgery team and here we remove the kidney with this part of the liver as well to make sure we got all the tumor on this is considered T4 T stands for tumor T4 means invasion into adjacent organs this is a curve called Kaplan-Meier curve and one of my colleagues Dr. Chapin will describe this in a bit of detail later today on the y-axis you have survival on the x-axis here you have just time the lower the curve which is T4 the higher the chance of not surviving this disease so here you see T1a this is the these are the tumors that Dr. Matin just described these are the small localized tumors the T4 is this curve here which is the bottom curve this is our experience here over a period of 16 years with 30 patients that we thought had invasion into other organs this is why we're using the word clinical so we looked at the CAT scans it seemed that there was invasion into other organs we took all these patients to surgery and thankfully only 40 percent of these patients had true invasion to other organs so in other words 60 percent of the patients did not have such invasion so these are patients who are considered to be over stage so again we thought they were T4 or invading other organs we took them to surgery and found that 60 percent of them did not the most commonly invaded structures as I wrote here are colon, pancreas and diaphragm but there could be invasion to other organs such as small intestine or major vessels as well and as you could see here the recurrence of the disease is higher if you have true invasion into other organs the average is about two months of the cancer coming back if there is true invasion versus about one year or more if there is no true invasion into other organs again this is another curve that I just showed and again saying the same thing that survival is lower if you have true invasion and the risk of recurrence of the tumor is higher if you have true invasion into adjacent organs and we found here that other factors that affect survival in this patient group are invasion into lymph nodes so typically if the tumor has gone to the lymph node the survival is lower and again these are the summaries from this study is that 60 percent of the patients initially thought to have invasion into other organs were found not to have such invasion when actually they were taken to surgery and we could not really predict who these patients are so we basically have to take these patients to surgery in order to find this information but if you think about it the other way if we don't take these patients to surgery we are letting down possibly 60 percent of the patients that we're not operating on because really they didn't have any invasion and here just to show you that the recurrence rates are higher if you have true invasion and still a significant proportion of patients did benefit from such aggressive surgical resection now moving on to the third topic of locally advanced disease this is the spread into lymph nodes this is a large tumor here you could see on the CT scan of invading the right kidney again this is the same tumor with a lot of lymph nodes being involved and this patient had surgery with complete removal of the tumor and complete removal of all the lymph nodes there was you know as you could see in this picture the liver which is here is very close to the kidney and it might look like it's invading but there was no invasion at all into other organs just the lymph nodes however the presence of spread into lymph nodes is a serious condition it does decrease the survival of our patients and this is the average five-year survival can be anywhere from 0 percent up to 20 percent in this patient population who has invasion of the lymph nodes and this is our experience with removal of kidney tumors such as the one I just showed who have only invasion of lymph nodes but no spread anywhere else so we looked at our database of patients we have about 2,500 patients who had no metastatic disease this is where the M0 stands for M is for metastasis and we found that 2.7 percent of the patients had positive lymph nodes which is spread to the lymph nodes without evidence of spread anywhere else in their body the average age is again the same as I showed earlier but 58 the tumors are large about 11 centimeters most of the patients have good performance status meaning that they don't feel anything for the most part but we have here about two-thirds of the patient have some sort of a local symptom maybe a little bit of pain or maybe some blood in the urine and here you could see that when we take these patients to surgery the results after surgery the survival is about 37 percent at five years which is a good number considering that these patients had aggressive spread of the tumor to the lymph nodes and the recurrences that happen after surgery you see about 50 percent of them happening early on but about one-third happened after one year so in that one-year period these 33 percent of the patients had no disease and the locations of the recurrence if the recurrence is meant to happen about 40 percent happens in one location and the rest occur and about in more than one location and this is what we found as far as the factors that can predict were how do we know if the patient's going to do well or not if they have the papillary histology as I mentioned earlier I mentioned the clear cell type which is the most common type the papillary histology is the second most common type so we found that if you have the papillary type of tumor if you have only one lymph node involved and not more this actually is a good thing that you might have longer survival however if you have the sarcoma type this is a very aggressive tumor and that could decrease survival and the better the patient feels the better the patient will do after the surgery so the patients who feel bad before going to surgery sometimes don't do very well after the operation and again this is the result and patients who had an operation about 45 percent of the patients had no disease at 12 months on average and about 22 percent were disease free on long term at a median or an average follow-up of about three and a half years so again a group of this patient population benefits from aggressive surgical resection and we have some ways albeit a bit crude ways to try to predict which patients might benefit from such an aggressive operation so again surgery does help a group of patients with node positive disease especially if there is no spread elsewhere and these are the predictors of who might benefit from such an aggressive resection again it's patients who have a papillary type patients who all the disease have been removed surgically with negative margins if they have a low number of lymph nodes if there is no sarcomatoid disease and the patient has a good performance status which means the patient is doing well in functioning normally and the last and the fourth topic is the topic of local recurrences again this is for patients who had surgery already and then during follow-up were discovered to have a recurrence in the area of the operation so if they had a right kidney removal or as in this picture here a left kidney removal you could see here there is a recurrence of the tumor where the left kidney was again we looked at our database and this is our own experience here of over of almost 3000 patients who had complete nephrectomy with the intent of cure and we found that actually a very small percentage had local recurrence 1.8 percent of this large number of patients had a recurrence at the area of the operation about 60 percent of the patients had symptoms these symptoms could be either local such as pain or blood in the urine or what not but some patients have systemic symptoms meaning fever or weight loss or just not feeling good and from our study of 54 patients we found five risk factors that tell us that the patient might not do very well after surgery and these are a large tumor a large size of a recurrence if the margins were positive which means that the tumor was not completely resected again you see here the theme of the sarcomatoid element if you have a sarcomatoid tumor typically the recurrence rates are higher and if you have these two blood tests the LDH and the alkaline phosphatase being abnormal so if you have none of these five risk factors the average survival is very good it's 111 month if you have one of these risk factors it's about three and a half years and the average survival if you have more than one risk factor is typically less than a year and this is from the study that we found that disease recurred in about two-thirds of the patients after aggressive resection and the isolated relapse or recurrence in that same location is about 15 percent the survival without a recurrence was about a year on average and the survival from a cancer standpoint was about five years in this patient's sub-population again this is a very rare entity as I mentioned 1.8 percent of their patients just as a final summary of all these four topics aggressive and complete surgical resection when feasible should be done or should be considered in patients who have a good performance status again patients who are feeling well and functioning normally and especially if they have limited spread elsewhere limited metastatic disease so if the disease is in the area of the kidney and the abdomen we should definitely consider aggressive and complete removal as I showed from one of our studies unresectable kidney tumors are extremely rare in other cancers this is a more common problem but a tumor of the kidney that is not removable by surgical technique is extremely rare so typically if somebody tells a patient your tumor cannot be removed because it's unresectable that patient should at least seek a second opinion just to make sure that this is the right thing as I showed you we are fooled by the CT scan and 60 percent of the times that we think the tumor is invading other organs but it's really not and the only way to know is to do the operation and for the surgeons it's very important to be familiar with distorted anatomy with these large tumors and with these large lymph nodes and with advanced surgical techniques to try to get the best outcomes for our patients and this is truly a multidisciplinary teamwork this is not the work of only the urologist this is the work of the radiologist who's helping us identify things before surgery our colleagues from medical oncology to see if the patients need treatment before or after surgery and also our colleagues from other surgical departments such as the intestinal surgery the liver surgery the vascular surgeons who help us with these types of big operations and again I think it's very important to avoid surgical nihilism in patients with locally advanced kidney cancer so just because you have a very big tumor doesn't mean that there is not a potential for cure and that's why if a patient is told you can't have surgery or you shouldn't have surgery or we can't remove the tumor the safest thing is to just talk to another doctor and then get their opinion just to be sure that this is truly the right thing to do or not thank you very much for your attention so I think we'll we'll hold off on questions until the the part where we do the case presentations I think that'll be the easiest so I'm going to talk today about the promise of adjuvant and neal adjuvant therapy and kidney cancer so I think this point has been made already but kidney cancer is a real problem in the United States greater than 50 000 annual cases about half of these are localized disease but about half either present whether we'll develop metastatic disease in the course of their illness prior to 2006 we really didn't have a lot to offer patients those who had localized or locally advanced disease were offered nephrectomy and those that had metastatic disease were typically offered nephrectomy followed by some form of systemic therapy which largely was immunotherapy we'll hear more about that later but the median survival for patients was less than a year but it's a whole new world in the treatment of kidney cancer and you'll learn more about this as the morning goes on but we now have many arrows in the quiver to offer patients who present with metastatic disease and it's really just a new horizon with regards to outcome for patients improve survival improve progression free survival due to the employment of these agents but while these are base hits they are not home runs and what we've learned is that these agents are not curative they control the disease for a period of time but the cancer ultimately learns to outwit these agents and grow back with a vengeance and although we do have multiple choices to offer patients ultimately patients who present with metastatic kidney cancer are destined unfortunately to die of their disease so you know probably the most common question that I get asked by patients who are either getting ready to undergo surgery or have just undergone surgery is am I going to need radiation am I going to need chemotherapy so what they're asking is am I going to need adjuvant therapy or neo adjuvant therapy adjuvant therapy means to give some form of therapy after surgical resection of all visible disease in the hopes of decreasing the risk of recurrence neo adjuvant therapy means to give some form of therapy prior to surgery to potentially downsize or downstage the primary tumor and make the surgery easier and also it may eliminate micrometastatic disease that has already gone on to spread and then there's presurgical therapy which means to give therapy in the metastatic setting prior to surgery as a prior removal of the primary tumor in many ways this can be used as a litmus test where you only operate on the patients who are doing well with their systemic therapy and showing a response so here's a summary slide of where we stand with regards to adjuvant therapy so when you ask am I going to need chemotherapy after my surgery to decrease the risk of recurrence that unfortunately the trash heap is replete with numerous agents that have been tested in the adjuvant setting radiation tumor embolization energy ablative therapies hormonal therapies variety of different immunotherapies a whole host of different vaccines we even did a trial with the drug the litimide and unfortunately not one of these agents has proven to be beneficial in the adjuvant setting and as I showed you we're now in the era of targeted therapy so where do things stand with regards to the efficacy of targeted agents in the adjuvant setting well there have been numerous trials that have been performed this is one such trial this was with a drug called rencor X and basically it's an antibody against a protein that is not specific to kidney cancer but highly expressed in kidney cancer called carbonic anhydrase nine and basically this was a randomized trial where half the patients got saline and half the patients got this antibody and then they looked and said does this decrease the risk of recurrence and the answer unfortunately again is no patients that receive the antibody did not have a decreased risk of recurrence relative to those who got placebo one other use of this agent however that does appear to be promising if the company will continue its development is the so-called kidney cancer specific PET scan where this antibody can be used to both identify the histology of a primary tumor in situ but also potentially identify metastatic disease that may not be clinically evident on a conventional radiographic imaging and this is the assure trial and the Anderson was the largest accruer to this trial it was a randomized trial looking at patients who had locally advanced disease that underwent surgical resection and they were randomized to either one year of synitinib one year of serrapinib or placebo with the primary endpoint again being disease free survival this trial has completed a cruel meaning that all the patients we need to answer this question have in theory been enrolled in the trial and taken the drugs and now we're just basically sitting on our hands waiting for the result what we have learned from this trial however we don't know whether these agents are effective in decreasing the risk of recurrence but they are toxic and toxicity in the adjuvant setting is not really well tolerated as it is in the metastatic setting and in fact in this trial almost half of the patients dropped out not because their disease recurred but because of toxicity and my concern about this trial this was a huge national effort but my concerns about this trial are at the end of the day if the trial is negative is it negative because the drugs don't work or is it negative because not enough patients took the right amount of drug for the right amount of time or dropped out because of toxicity the hope is that this trial is going to read out in the next couple of years this is the S-track trial this was a trial sponsored by Pfizer and I think of all the different trials that I'm going to show you this morning this trial has the best hope of telling us whether or not synitinib in the adjuvant setting is effective again patients were randomized to one year of synitinib versus placebo but the compliance rate for this trial meaning the number of patients that actually completed the therapy is significantly higher than it was in the assured trial again we're waiting for the answers on this trial as well this is the source trial this is ongoing over in the United Kingdom and I think also in Canada this was a randomized trial looking at one year of seraphim versus three years of seraphim versus placebo this was an extremely difficult trial to enroll to I think even patients with metastatic disease have a hard time tolerating three years of seraphim and memorizing those in a locally advanced setting you can see that it said primary result was due August 2012 it's currently what April 2014 this trial hasn't even completed the cruel yet this is the so-called protect trial this was sponsored by GlaxoSmithKline and this was an adjuvant study looking at the role of pazopinib in the adjuvant setting patients were randomized after surgery to one year of pazopinib versus one year placebo again this trial has completed a cruel we're waiting to see what the results will be probably in the next three to four maybe five years and that's really the challenge with these adjuvant studies is that they take a long time to accrue patients but then even longer to wait for patients disease to recur to give us an answer as to whether or not these drugs are effective in this setting there currently are two trials that are open and accruing patients this is a so-called Everest trial this is a SWAG or Southwest Oncology group study where patients are randomized to one year of Everolimus which is an mTOR inhibitor versus placebo this is again currently accruing patients and then this is the so-called ATLAS trial again Pfizer we're related to Pfizer where patients are randomized in one-to-one fashion to three years of accident which is one of the new targeted agents you'll hear more about today versus placebo so you can see that there's a tremendous amount of interest and a tremendous amount of research ongoing in the adjuvant setting to determine whether or not there is a drug that decreases the risk of recurrence but in May 2014 or sorry April 2014 the standard of care following surgery for locally advanced disease is observation radiation therapy chemotherapy don't work so now let's talk a little bit about neoadjuvant therapy and this is not a new concept although it is very new in the treatment of kidney cancer and you know 10 years ago the idea of neoadjuvant therapy for kidney cancer was a pipe dream we had no effective agents that reliably were anti-tumorol but it is the standard of care for a variety of different locally advanced solid tumor malignancies we hear about it in patients who have breast cancer bladder cancer esophageal cancer pancreatic cancer rectal gastric and so forth there have been numerous phase 2 trials and other malignancies such as prostate and sarcoma so why not kidney cancer well at least traditionally it's been a relatively chemoresistant tumor the chemotherapies that we give for things like lung cancer and breast cancer don't work in kidney cancer and we really had no effective systemic therapies that reliably impacted tumor biology but as I've alluded to this it's a new world in the treatment of kidney cancer and over a period of approximately five years seven new treatments were approved for the treatment of kidney cancer so that now we have many arrows in the quiver that we can aim at this cancer so here's a typical case it would I would see in my clinic a 55-year-old white male presents with blood new urine he has a few comorbidities hypertension hyperlipidemia he has a staging evaluation which includes a bone scan and a CT chest both of which are negative and again you can see a locally advanced tumor involving the left kidney so just here's the locally advanced tumor involving the left kidney here it is in sagittal section and we all know that stage determines outcome I mean it is the most important predictor of outcome for patients so this gentleman would be classified as a stage 3 and you can see here that his five-year survival is about 60 percent but if you're a glass half empty kind of person that means that he's got a 40 percent chance that his cancer is going to come back and he's going to die of kidney cancer so what are his options well radical nephrectomy followed by risk-based surveillance that would be considered the standard of care his risk of recurrence again is somewhere between 40 and 60 percent and if he does recur he's not likely to be curable he could do radical nephrectomy followed by adjuvant therapy but this can only be done really in the context of a clinical trial because as I just got done telling you there are no effective adjuvant agents he could enroll in the atlas or the everest trial which are currently ongoing but he's got a 50 percent chance of getting a sugar pill he's got a greater than 50 percent chance of either reducing his dose or stopping therapy early due to toxicity and to be honest except for the tincture of time there's really no way to assess efficacy if he remains NED is it because he had a fantastic surgeon or is it due to the drug we may never know so why neoadjuvant therapy well preoperative systemic therapy may eliminate micrometastatic disease and improve prognosis it may downsize or downstage the tumor allowing us to perform nephron sparing which we heard from dr. matine is critical or allow us to do a minimally invasive approach to a large tumor and we can also look at evidence of response to therapy to potentially influence therapy in the future if the patient does demonstrate evidence of metastatic progression so why not neoadjuvant therapy well maybe your tumor didn't read the book and didn't know that it was supposed to respond to the therapy and may progress locally or regionally or even systemically and we may lose that window of opportunity for cure but i would argue with you that if your tumor is so bad that it doesn't respond to the current agents that we have to treat kidney cancer you're probably not curable anyway and it's also possible that the toxicity of therapy may increase the morbidity of surgery you have a patient with a large tumor that's already a man eater and you beat them up with systemic therapy they don't make great surgical cases so for a neoadjuvant therapy to take hold i would argue that it has several hurdles to jump just like partial nephrectomy did 20 years ago patients who presented even with a one centimeter tumor usually underwent these huge nephrectomies until partial nephrectomy was demonstrated to hold oncologic equipoise or equivalent cancer control to radical nephrectomy and then it had the added benefit of being nephron sparing and now we have minimally invasive approaches as you've heard well neoadjuvant therapy has several hurdles it has to be safe we have to demonstrate that it doesn't patients don't have disease progression or increased surgical morbidity associated with surgery it has to improve patient outcomes and you know as you just heard from dr karam it is the rare patient that has an unresectable tumor but if you can get the tumor to be smaller perhaps you can increase utilization of nephron sparing and minimally invasive approaches so is neoadjuvant therapy safe well these are two patients of mine that receive pre-surgical therapy so they have metastatic disease but got one gets uh bevacizumab and one got synitinib in the pre-surgical setting and you can see on these uh radiographs that this patient had complete abdominal wall dehiscence this is actually his greater omentum which is a piece of fat hanging off the stomach sitting on his anterior abdominal wall and this is a woman who received bevacizumab and three months out from surgery she coughed and heard something give and all this white stuff here is her small intestine sitting in the sub queue you could literally see it peristalsing on her abdominal wall so there could be real problems with complications associated with this approach well brian chapin who's a member of our faculty and speaking later uh today when he was a fellow did a retrospective review of our experience with pre-surgical therapy and asked the question is it safe looking at complications within the first year of surgery so he compared a group of patients 70 in fact who had pre-surgical therapy to a group of patients who had upfront surgery and asked was there a difference in the rate of complications and the short answer is no there is not a difference in complication rate between those that had upfront surgery and those that receive pre-surgical therapy however there was a significant difference with regards to the type of complications those patients who received pre-surgical therapy were much more likely to have a wound complication relative to the patients that had upfront surgery and they were also more likely to have delayed complications but in fact pre-surgical therapy was the most important predictor of having a wound complication in this series with an odds ratio of almost four above four but in terms of predicting overall complication rate receiving pre-surgical therapy was not a predictor of complications in this setting so again you're more likely to have wound complications with pre-surgical therapy but in terms of the overall rate of complications they were equivalent between the two groups so then we asked the question okay if patients are more likely to have a wound complication is there anything that we can look at that might predict it so that maybe at the time of surgery we can do something to the wound put in retention sutures leave the staples and longer put in more unobservable sutures to decrease the risk of them having a complication and we found that those patients who had a decline in their serum albumin which is a blood test that we can get those patients were more likely to have a wound complication and therefore we could do something at the time of surgery to reinforce their wound one of the other things we noted from this study which was retrospective was that those patients who had pre-surgical therapy did not have a different survival from the group that had upfront surgery so what that tells us is that with this approach we're not we're not hurting people we may not be helping them but we're not hurting them by using this approach and studying it in this setting and that's shown graphically here so what about primary tumor downsizing or down staging are we seeing that with pre-surgical therapy well classically in the era of immunotherapy and these are patients that were treated with entry lukin 2 nobody had a primary tumor response and in large part that's why we're doing cytoreductive nephrectomy something you're going to hear about in subsequent talks today for patients with metastatic disease but there are numerous reports in the literature showing things like this in patients who receive targeted therapy so you can see here this patient has a locally advanced tumor involving his right kidney as well as one involving his left kidney and he receives synitinib and went on to have bilateral partial nephrectomy saving his kidney and improving his overall renal function and this is a patient of Dr. Matine's again locally advanced tumor involving the left kidney here with bulky lymph node involvement and went on to receive synitinib and you can see a dramatic shrinkage in the tumor and loss of the lymph nodes and this patient actually went on to have a laparoscopic nephrectomy and this is a patient that we treated with exitinib something I'm going to talk about in a few minutes again locally advanced tumor involving the left kidney that shrank dramatically with exitinib therapy and here's the surgical specimen you can see a huge reaction around the kidney tumor and this is one more example so the question is are these anecdotes or can we reliably rely on these agents to downstage tumors because I would argue let's get it to everybody and then maybe we can increase the utilization of nephron sparing well this was a study that was published some time ago looking at patients who were treated with their primary tumor in place with synitinib and you can see that the response rate in the primary tumor was about almost 25 percent with a mean volume reduction of 31 percent well we published a study a few years ago looking at 168 patients who were treated with their primary tumor in place these are the different agents that the patients received the vast majority receiving synitinib which was the standard of care and remains and you can see that the overall response rate unfortunately is a very disappointing 7.1 percent okay so that means that you have a 10 centimeter tumor if you give pre-surgical targeted therapy it's going to shrink to nine centimeters kind of a let down and while there were some patients who had dramatic progression and some patients who had dramatic regression the overwhelming majority have little of any change at all so what about patients who have a venous tumor thrombus we heard from dr karam how difficult those surgeries can be can we maybe shrink the tumor thrombus and make the surgery easier well we had 48 patients in this study that had evidence of tumor thrombus and again unfortunately the overwhelming majority of them had no response 75 percent at stable disease 15 percent of patients actually progressed on therapy and only 10 percent of patients actually regressed the good news is however treating patients didn't hurt them there were no cases of pulmonary embolism so i would argue that the initial body of evidence would suggest that this significant primary tumor downstaging is not going to be realized with the current generation of targeted agents although the jury is out with regards to newer agents so i'm going to show you some data that's kind of exciting in that regard so we recently completed a trial and this was just published in european neurology looking at the role of neoizminexitinib in the locally advanced setting so we took patients that did not have metastatic disease had locally advanced tumors treated them for three months with exitinib and then took them to surgery so i want to give you an idea how this conversation went so so i was the primary principal investigator of this trial so we have the guy sitting in front of us he has a locally advanced tumor probably presented with blood in his urine and it's curable with surgery and i say to this guy we want to give you this drug it's going to make you feel like crap may work may not work we don't really know we're going to give it to you for three months your tumor may in fact progress while you're on therapy and then we'll take you to surgery otherwise we could take you to surgery now and cure you what do you say so i actually mire the bravery of the first guy that went on this trial because once we could demonstrate that we were seeing responses it was much easier sell to patients and then we were able to rapidly accrue to this trial so patients started a dose of five milligrams twice a day for 12 weeks and they titrated up to 10 milligrams a day and we continued the drug until about three about day and a half before surgery 24 patients and there's the clinical criteria right there all of them were stage three at the time of presentation 22 patients stayed on drugs for the whole three months one patient stopped at 11 weeks all 23 patients underwent surgery is planned without delay one patient had to stop at seven weeks due to toxicity and was taken to surgery early and in this trial we had a 46 percent unheard of 46 percent partial response partial response means that the tumor shrank at least 30 percent and 13 patients had stable disease and importantly nobody progressed while they received the drug so these are the tumor plots and you can see from this that the overwhelming majority of the response is within the first six to seven weeks and that the following six to seven weeks there really wasn't much of an additional response and that's important to us as clinicians because it when it tells us if we don't see a response early we're not going to see a response and it's time to move on and this is a waterfall plot again demonstrating the response that we saw so a partial response is greater than 30 percent and here you can see that almost half the patients had that significant response which from a surgical perspective I would argue is clinically significant so 19 patients were treated with radical five with partial 19 open five laparoscopic and you can see the clinical or the pathologic stages there now this drug was not without its toxicity significant number of patients had hypertension some had hoarseness the vast majority had fatigue some patients had hypothyroidism but all of these toxicities were reversible and I would argue that three months of toxicity before surgery versus one year of toxicity after surgery is probably better tolerated and this is another example of response I think I showed that so we concluded that exidine was well tolerated in the neoadjuvant setting that it showed downsizing activity when given for 12 weeks prior to surgery in that adverse events were common but easily manageable so here's where we stand effective adjuvant and neoadjuvant therapy do not exist for kidney cancer in the year 2014 toxicity of that targeted therapy in the adjuvant setting is poorly tolerated and may impact efficacy effective neoadjuvant therapy may increase the utilization of minimally invasive and nephron sparing surgery which we learned is important neoadjuvant and pre-surgical approaches may also be used as a litmus test to better select patients for surgery but you should leave here knowing that adjuvant and neoadjuvant approaches are not the standard of care and clearly they need further testing in the context of clinical trials thank you very much for your attention so our next speaker is dr. Nazar Taneer who has promised me he's going to stay on time and he's going to give us an update on targeted therapy for metastatic kidney cancer good morning everybody and thank you chris for the introduction and i'd like to also thank the kca organizer organizes the leadership of bill pro and gary konoski for putting this together these are my disclosures so as you saw in dr wood's talk the treatment landscape for ian sarcasenoma has witnessed a revolution in a very short period of time in seven years we saw the approval by the fda of seven agents after a drought of 13 years since the approval of high dose r2 within a month so raffinib and sunitinib came to the market in december 2005 for so raffinib and in january 2006 sunitinib was FDA approved in 2007 the first mtor inhibitor temsir alamos was approved and in 2009 we saw the approval of three agents or three therapies ever lemus vivacizumab plus interferon alpha and pazatinib and in january 2012 exitinib was FDA approved this slide summarizes for you the targeted therapies that are licensed in the us for treatment of metastatic renal cell cancer i'd like to draw your attention that two of these ever lemus and exitinib are approved for the second line or salvage therapy and the other five are approved as you see in the first in the right hand column for the treatment of metastatic renal cell casinoma irrespective of line you see here the targets of these different therapies the root of administration five of these are oral to our intravenous and you see also the target of these agents now four of these are what we refer to tyrosine kinase inhibitors these are the drugs that are taken by mouth and they target the tyrosine kinase inhibitor specifically vgf receptor and two belong to the class of mtor inhibitors this is a summary of the first line phase three trials conducted for the metastatic renal cell casinoma the top two combined vivacizumab which is a monoclonal antibody against vgf and interferon alpha then pazapa nib sunita nib tyrosine and exitinib are tyrosine kinase inhibitors as i mentioned and tyrosinomas is an mtor inhibitor you see the control arm in the fourth column and then the number of patients enrolled on these trials on each of these arms and the primary endpoint i think i would like to discuss the bottom two trials first because these are drugs that were not approved for the indication that were conducted then and that's tyrosine and exitinib tyrosine and and exitinib are referred to as a novel or second generation tyrosine kinase inhibitors because they are more potent against the primary target vgf receptors and they are more selective they do not have the off targets the other kinases that the sunita nib sorapha nib and pazapa nib the older generation or first generation have that these two trials tyrosine and exitinib were compared to sorapha nib in the first line and you see the number of patients and they have they had for primary endpoint progression free survival they did not meet the primary endpoint because the exitinib had a 78 percent aim of improving progression free survival compared to sorapha that was an ambitious goal and this was the idea was to do the trial faster and to do it in a smaller number of patients and unfortunately the while exitinib had a longer progression free survival then sorapha nib it did not meet the endpoint of 78 percent improvement so it was not fd approved for the first line treatment of patients with metastatic clear salary and sarcosinoma tyrosine versus sorapha nib while the primary endpoint was met which was progression free survival and was improved with the second generation tyrosine versus sorapha nib however however the problem with the trial is that patients who were treated with sorapha nib in the first line had the opportunity to cross over after progressing on sorapha nib and receive tyrosine while patients who received tyrosine in the first line very few of them crossed over to receive a second line therapy so it ended up being when you look at survival it ended up being comparing a group of patients receiving one line of therapy and that's tyrosine versus a group of patients that received two lines of therapy therapies sorapha nib followed by tyrosine so the survival of the group of patients received sorapha nib was better than the survival of patients received tyrosine in the first line so that's why the fda did not approve tyrosine and we'll move on and discuss briefly the other trials starting with synitinib this was a phase 3 trial comparing patients with interferon alpha the old standard given at the standard dose and schedule 9 million three times per week versus synitinib 50 milligram daily on the standard schedule of four weeks on two weeks off it was a large phase 3 trial of 750 patients the primary endpoint was progression free survival and patients who were recruited to the trial if they had you see the box there of eligibility criteria predominantly clear cell and no process stomach therapy measurable disease good performance status and adequate organ function the secondary endpoints were overall survival objective response rate patient reported outcomes and safety and you see the couple in my curve showing that patients treated with synitinib presented here in blue had a better progression free survival a median of 11 months versus five months median progression free survival for patients treated with interferon alpha this was a statistically significant difference between the two arms then we have two trials combining B. vasusimab plus interferon these were very similar in design represented in this schema here one was conducted in the u.s. by the calgb inter cooperative group and included 732 patients and one was conducted mostly in europe by avoran the avoran trial it had 649 patients the difference between these two studies is that patients with avor on the avoran trial were required to have prior nephrectomy before enrolling on the trial and the treatment also comprised placebo in addition to B. vasusimab placebo for B. vasusimab whereas the clgb did not mandate prior nephrectomy and there was no placebo control primary endpoint of the trial was os secondary endpoints pfs objective response rate and safety and use as you see here in the two kaplan mark curves for the avoran study as well as the clgb trial study patients treated with the combination of B. vasusimab plus interferon had a better progression free survival represented in the green curve compared to patients who were treated with just interferon alpha or interferon alpha plus placebo however patients did not have a superior survival the survival of patients on these two arms was not significant and the reason was patients after coming off these two trials had the opportunity to receive other target therapies and that confided the survival same thing we saw with the previous trial i showed you with synodin versus interferon while there was a trend for improvement of overall survival in the patients treat with synodin compared to interferon alpha this was did not cross the threshold of becoming significant again because patients received other target agents after coming off and then there was 25 patients who crossed over from interferon to synodin the other phase three trial was the global this was a phase three trial of tensor almas the inventory inhibitor versus interferon alpha versus the combination of tensor almas plus interferon alpha the primary endpoint of this trial was overall survival patients were recruited who had any histological type of rcc 80 of those patients had the common type cleav cell or conventional histology and 20 had the other non-clear what we refer to as non-clear cell histology but importantly for patients to be eligible for the trial they had to have three or more risk factors to enroll in trial and here you see the kaplan-meyer curves again showing a separation of the curves patients treated with tensor almas had a superior survival compared to patients who were treated with interferon represented in blue or the combination represented in pink the median survival for patients treated with tensor almas was 10.9 months versus 7.3 months median overall survival for patients treated with interferon alpha an improvement of 49 percent so that led to the FDA approval of this agent for rcc the next study was the bazaupanin phase 3 study this was a study conducted or sponsored by glasco smith kline it was conducted mostly in europe patients had to have cleav cell histology but there were two cohorts of patients one cohort previously treated with cytokines and one cohort treatment naive there was two-to-one randomization in that two patients were randomized to receive bazaupanin versus placebo the primary endpoint was progression free survival and here are you here are the curves for patients treated with bazaupanin represented in the yellow curve the median progression free survival was 11 months again similar to what you saw in the study with sunitinin versus interferon alpha patients treated with placebo had immediate survival of about three months again significant difference and this was that to the approval of bazaupanin again as we as I mentioned with the other trials 48 percent of patients treated with placebo when they had progressive disease with placebo were were given the opportunity to cross over and receive bazaupanin after progression and this led to again the confounding impact on survival when you look at median survival for these two cohorts there was no statistically significant difference in overall survival again because of the crossover and subsequent therapies patients after the study so of what I mentioned it looked like the two front runners for the treatment of metastatic RCC in the first line where sunitinin where you had the best results and bazaupanin where you had also the best results so these were the two front runners although bivacizumab plus interferon had you would think comparable efficacy it did not catch on in terms of applicability in the clinic because patients had to receive would have to receive an infusion every two weeks plus injection of interferon three times per week so it was no surprise that GSK decided to have this trial that we care compares trial comparing the two front runners bazaupanin versus sunitinin for first-line treatment of metastatic RCC this was a large phase neutral of 1110 patients uh conducted in multiple continents it had the design of non inferiority for progression free survival in other words they wanted to show if bazaupanin is non inferior to sunitinin when it comes to efficacy looking at the progression free survival as primary endpoint and there were secondary endpoints overall survival objective response rate duration of response safety and quality of life and here are the results bazaupanin was found to be not inferior to sunitinin and uh if looking at the progression free survival which was the primary endpoint and when you look at the secondary survival which is important secondary endpoint the sort of median survival for patients treated with bazaupanin and sunitinin was similar about two and a half years however very importantly there were differences in toxicity and quality of life in 16 out of 16 quality of life domains bazaupanin was felt to be better tolerated by improved quality of life tools compared to sunitinin and toxicity favored bazaupanin because it had patients had less fatigued and less hand food skin reaction less mind of suppression the next study that uh jsk sponsored and this was recently published in in the uh journal of clinical oncology this was a patient preference it was a double blind design comparing bazaupanin versus sunitinin in a double blind fashion so the patient didn't know what they were taking and the physicians treating did not know what they were taking and ultimately patients were told at the end of the study which directed they prefer was it the first one which was given for 10 weeks then two weeks break then they switched or the other way around so this was 160 patient trials so it was a phase two trial and the results were in favor of bazaupanin by a margin of 70 percent to 20 percent also in blue this was tracked by the physicians 61 versus 22 percent of patients again of physicians also uh preferred or voted for bazaupanin as the preferred agent but the story doesn't end here because quality of life tools were administered in the previous trial compares at a time at the end of the cycle for sunitinin 29 days every 29 days and that for patients who have received sunitinin will tell you that this is the peak when they have the most adverse events so now after eight years of sunitinin we have alternative uh set schedule to give the strike instead of the standard four weeks on two weeks off retrospective study from our institution as well as other institutions have shown that patients who receive sunitinin with the two weeks on one week off schedule have less adverse events and there is a suggestion that patients will have a better survival because they can stay on treatment longer so the the jury is still out which would be the preferred agent up front i think there is no question that both drugs are good drugs now what about second line and beyond i will go quickly through those phase three trials this was the first trial with the target agents the target trial compared so raffinib versus placebo in patients who had cytokine and prior therapy the primary endpoint was os secondary endpoint was progression free survival and here are the coupling mild curves in blue our patient's treatment with sarafinib in red our patient's treatment with placebo there was a statistically significant difference in progression free survival patients with a treat with sarafinib had immediate progression free survival of 5.5 months compared to 2.8 months but the overall survival began because again as happens with the other trials there was a crossover at progression there was no statistically significant difference between the two arms the record one phase three trial compared iverolimus after cytokine or sarafinib versus placebo this was a two to one randomization again twice the number of cases were randomized to receive iverolimus plus best supportive care versus placebo plus best supportive care the primary endpoint was progression free survival and again the results were in favor of iverolimus over placebo again these are patients who were treated previously with a tyrosine kinase inhibitor either sarafinib or synatinib the other study phase three trial was the access study and it randomized patients to receive either exitinib or sarafinib after receiving either synatinib first line or bivacizumab plus interferon or tyrosine or cytokine and then the results are here patients treated with exitinib represented in the yellow curve had an improved progression free survival with a median of 6.7 months compared to sarafinib with a median of 4.7 months however it's important to note that the best results were in patients who received exitinib after receiving prior immunotherapy so the median progression free survival with exitinib after immunotherapy was 12 months if you look at given exitinib after synatinib the median progression free survival was 4.8 months but all of these were in favor of exitinib there is an important study that compared thymyserolimus and sarafinib so this is the first time we're comparing an mTOR inhibitor versus sarafinib in the second line after synatinib so all these patients here were treated with synatinib first and had progressive disease and then now they're assigned to receiving either the mTOR inhibitor thymyserolimus or sarafinib the primary endpoint was progression free survival and then when you see the curves although numerically thymyserolimus had a better progression free survival median 4.28 versus 3.9 this was not statistically significant but what was statistically significant and of concern was the survival was surprising and anticipated in that patients who were treated with sarafinib after synatinib so tki after tki had a four month difference improved survival compared to patients who received thymyserolimus so suggesting that maybe given a tki followed by tki a tyrosine kinase inhibitor against vgf would be a better strategy than giving a tki followed by an mTOR inhibitor the last phase three trial i would like to show is this golds trial it's a phase three trial of duvitinib versus sarafinib in patients with clear cell ryan sarca sinema who had a tyrosine kinase inhibitor for first line an mTOR inhibitor evronymus for the second line and then they are randomized to receive either this bfgf receptor inhibitor because bfgf is was implicated to be a pathway responsible for resistance to that to angiogenesis inhibitor versus sarafinib the the results were negative in that the progression free survival was not significantly different between the two arms patients receiving third line duvitinib the bfgf receptor inhibitor had a median pfs of 3.7 months compared to 3.6 months with sarafinib survival median was 11 months for both arms and the response rate with each agent was very low 4 percent so what about combinations and sequential therapies in one word there is no combination of two target agents that is more helpful or more efficient more effective than a single agent except for the combination of bfgf plus interferon alpha that i discussed so the question is if patients do not achieve a complete response does it matter what you start with and here are trials that are asking addressing that question this is a trial conducted in germany was presented two months ago at the asco g u comparing two sequences of two tyrosine kinase inhibitors sarafinib followed by synitinib versus synitinib followed by sarafinib the results were not surprising while the patients who received synitinib first had a two-month improvement of their progression-free survival compared to sarafinib when you look at time on therapy from first line to second line there was no significantly significant difference between the two arms the record three is a phase two trial comparing an mtor inhibitor everolimus versus synitinib this was presented at asco last year it has not been published yet the results show superiority of synitinib over everolimus in the first line and there is also concern here similar what we saw with the mtor sac when we give them sarafinib in the second line after a tyrosine kinase inhibitor the patients who received everolimus first followed by synitinib there was a trend for inferior survival compared to patients who received synitinib followed by everolimus now toxicity is an unpleasant and unwelcome thing patients have to go through when they're receiving these therapies but this is a double assort patients have if they have developed the hypertension or hypothyroidism hand for skin reaction fatigue with these tyrosine kinase inhibitors we looked at these and we find that patients who have these actually do better than patients who do not develop these toxicities so while toxicities maybe are definitely untoward and unpleasant and unwelcome they suggest that patients who develop these toxicities have a better outcome or response respond better to these therapies we and others showed that in response to mtor inhibitors developing pneumonitis is associated with also improved survival in patients treated with the mtor inhibitors these patients who develop hypercholesterolemia while receiving everolimus or termsrolemus also are predicted to to do better what about monk mursal these are this is the list of the 2004 WHO classification of the renal tumors you know papillary chromophob translocation renal medullary collecting duct mucinous tubular spindle cell and others what do we do for these patients as I showed you the majority of the trials in RCC have been conducted in clear cell what about the non-clear cell in a word there is no established therapy for the non-clear cell that's why it's important to to do these clinical trials and these this is a list of some of these ongoing phase two trials in non-clear cell RCC I'd like to briefly show you some of these trials we're doing here at MD Anderson this is the ESPN trial or everimus versus synitinine prospective evaluation in non-clear cell RCC we just completed a cruel on this trial and it's been selected for oral presentation at ASCO patients with non-clear cell RCC with metastatic disease are randomized to receiving everimus the mtor inhibitor versus synitinine and at disease progression that cross over results will be presented ASCO so maybe next year I'll share with you those results we are still conducting the star trial and this is a sequential two-agent assessment in the RCC in patients with clear cell who have already had their nephrectomy we're looking at six sequences we chose three drugs one representing each class bivisuzumab representing the antibody against the EGF was open in the tyrosine kinase inhibitor and everimus the mtor inhibitor the goal and the goals of these trials is to come to precision medicine try to identify patients who respond to one of these agents and try to understand why patients who respond to the to one of these agents lose their response and have progressive disease so this is a very tissue rich trial with a lot of correlative studies that will be crucial and informative once we complete the trial we're at 170 patients for a total of 240 patients the TEMPA trial is an ongoing trial for clear cell RCC patients who have poor risk disease and it's comparing Pazopanib versus the standard of care for patients with poor risk the TEMPSerolomus we have 30 patients enrolled on the trial toward a goal of 90 patients so conclusion we have seven target agents that have been approved improvement in progression free survival has been shown with all agents and improvement in us with one agent TEMPSerolomus but complete responses are rare early and active management of adverse events will minimize those delays those reductions or treatment discontinuations and may impact long-term benefit adverse events may be predictive biomarkers of therapeutic benefit sequential therapy is the standard of care in 2014 but the optimal sequence tyrosine kinase inhibitor followed by tyrosine kinase inhibitor or tyrosine kinase inhibitor followed by mTOR inhibitor remains to be determined there is no established systemic therapy for advanced non-clear cell RCC unfortunately but the hope is that insights into the biology of rea sarcasinoma will be essential and will help us to identify relevant targets and improved therapies there is still a role as you will hear later from my colleague dr gal for old immunotherapy will hide those are two and there is a promising wave of agents on the horizon with the immune checkpoint blockade nevolumab and epidemumab and they represent the next strategy for achieving a breakthrough in the treatment of metastatic rea sarcasinoma trials combining novel immune therapies with each other and target therapies are ongoing in the era of target therapy is there a cure for a patient with metastatic rea sarcasinoma I would like to finish on a positive note because I'd like to leave you with a message of hope this is a patient that I saw from Pensacola Florida eight years ago presented with hematuria weight loss left very crusade and work up showed a mass in his left kidney we were going to enroll him on one of the trials doctor would showed you pre-surgical trial with b vassisi man unfortunately we found he had metastasis in the brain so he was not eligible so we went on and treated them with seraphim because that was the first agent that came out and he received it for 16 weeks had transient response and had progressive disease and developed in addition to the brain metastasis and lung metastasis which I'll show you he developed metastasis in bone and liver so we start them with sunitinib and you can see here after several months of treatment with sunitinib his metastatic disease and the lungs resolved metastatic disease in the brain resolved the primary tumor as you see shrank significantly and the metastatic disease and the lymph nodes improved as you can see in the liver resolved in the bone healed you could see the hole in his thoracic in his lumbar vertebra how the newborn formation brain without treating him for the brain with radiation whole brain radiation or surgery or gamma knife the tumors in the brain resolved and look at the tumor and then after five and a half years of sunitinib we decided we should take that kidney out although initially it would have been unwise to do surgery up front in somebody who has metastatic disease to brain lungs bone and liver so we proceeded when he developed hypertension after five years of therapy we stopped sunitinib and after we controlled his blood pressure went on and took his kidney out and there was no viable tumor in his left kidney I saw him two months ago two years after stopping sunitinib he has no evidence of recurrence next month will be two years since he had his nephrectomy he's eight years without recurrence I would like to end this because this is why we're here today to give you hope and I want to thank you personally you the patients and your families for your trust and for participating in our clinical trials you are the heroes who inspire us and remind us of the urgency of our research to make cancer history thank you okay why don't we uh why don't we go ahead and take a break and we'll reconvene at 10 o'clock you can go out and get some coffee and get some more breakfast and then we'll see you back here at 10 o'clock yeah it is let me see if I okay great let me just I think also we moved the podium a little bit forward it would be more too would be more behind him yep tell me maybe something's holding yeah I don't know what it is I don't want to force it that's good that helped a little bit see see before it was kind of I don't know how to describe it is when they looked when they look up I was getting you know as you could tell it was a sharp yes yes yeah I can see a little shadow here I got you do it again now it seems to be just that backlight okay that's nice pretty close okay so I think we'll go ahead and get started again with the next part of our conference so our next speaker is J.J. Gao who is one of our medical oncologists from MD Anderson you know it's funny Andrew Lucan too was approved for the treatment of kidney cancer back in 1992 and immunotherapy for the most part was the mainstay of treatment and was thought to be largely ineffective and now we had these targeted agents but you know everything old is new again immunotherapies on the horizon is probably one of the more effective treatments for the treatment of kidney cancer and Dr. Gao is going to give us an update on that Dr. Gao thanks Dr. Wood good morning everybody so I'm going to talk about immunotherapy for the treatment of metastatic kidney cancer today so as many of you probably know immunotherapy was regarded once regarded as an ancient therapy of you know almost the Jurassic period however recent progress in research has revived really revived the dinosaur in immunotherapy for treatment of cancer so I'm going to spend some time with you today to review the history of immunotherapy and more importantly I'm going to share with you some exciting data in the field of immunotherapy especially for the treatment of kidney cancer so why are we interested in immunotherapy well we know immune system can kill cancer cells however the immune system kill cancer cells in a different way from the traditional chemotherapy and the target agents first of all it's adaptable so when the cancer cell changes the immune system can also change accordingly second is specific so the immune system will target the cancer cells directly and spare the normal healthy cells third it has memory so as you know cancer cells can hibernate in your body for many years so even after 10 years of hibernation when these cancer cells wake up the immune system also wake up try to catch these cancer cells and there are quite a few reasons for us to develop immunotherapy as treatment for cancer patients first we know tumors with more infiltrating lymphocytes actually are associated with good prognosis second we know that mutations during cancer development and progression actually can create this new antigens and this new tumor antigens can be recognized by the t-cells and the immune system through history many immuno many strategies have been used for immunotherapy the earliest strategy was to just use bacteria stimulants to stimulate the immune system which i will talk about more in a moment the second one was to use cytokines to energize the immune system to kill cancer cells people also tried to use vaccines and adopt t-cell therapy so these two methods are not used for kidney cancer therefore i'm not going to talk i'm not going to talk about them today but i will spend the majority of time to talk about immune checkpoint blockhead therapy which really has shown some great potential for kidney cancer so the bacterial products were first used by william collie to kill uh to treat cancer known as collie's toxin so dr collie actually cured the first patient with this bacterial products over 120 years ago and the left hand it was found it was interfering alpha actually that was stimulated by this collie's toxin uh to to kill cancer cells and he treated quite a variety of tumors and the first the most to the tumors he treated the most was soft tissue sacoma and as you can tell from this data he treated more than 100 patients and over 50 of these patients can actually can live more than five years for kidney cancer he only treated six patients at that time three patients didn't have response the other three which is 50% actually lived more than five years so even by today's standard that dr collie was quite successful so why collie's toxin was not approved for for treatment of kidney cancer that's because it's too toxic so after patients receive this collie's toxin they have shaking chills they really become very talk very very sick therefore fda actually didn't approve collie's toxin for treatment of kidney cancer and then almost 100 years later people found il2 actually has activities against kidney cancer that's because il2 can stimulate t cells and the natural killer cells to kill tumor cells other than il2 interferon alpha and interferon beta were also shown to have modest activities against kidney cancer as dr tunir just talked about a moment ago so this is the high dose il2 data on a total of 255 patients 37 patients actually had response so of this 37 patients 17 patients had a complete response but please note of this 17 patients 80 percent of them lived up to 10 years and beyond and for those patients who had only partial response and there are 20 of them in total so only 30 percent actually only about 25 percent of them lived to up to almost 10 years so really il2 therapy offers the long-term survival potential for for patients however the response rate is pretty low so the complete response rate is lower than 7 percent the partial response rate is lower than 15 percent and it is again a very toxic therapy so many patients who receive idle high dose il2 have to be monitored in the icu setting therefore il2 therapy is really limited to the younger and healthier patients and then dr tunir already showed you this piece of data by combining interferon alpha and the bevacizum as you can tell from the table here the combination therapy actually can improve the progression survival of patients which means it delays the tumor recurrence or progression by about three months and because of this bevacizum and plus interferon alpha along with high dose il2 were approved by the FDA for the treatment of a kidney metastatic kidney cancer along with many target agents that were discussed by dr tunir just a moment ago so this is basically the timeline of the treatment options for renal cell casinoma so in 1980s il2 and interferon alpha were first shown to have activities against kidney cancer and then 10 years later high dose il2 was approved by the FDA and over the past 10 years seven to 10 years also there is just an explosion of these target agents which are really great options for treatment of of metastatic kidney cancer and because of these agents people's life people with metastatic disease the average survival has increased from you know about a year to more than two years and then this is the combination of bevacizum and plus interferon alpha however despite the recent success of these target agents we all know that many of these patients will develop resistance to the treatment just within months so after that we have to switch to another agent so the question is do we have any better therapy with longer with long-term survival potential and that's when the immunotherapy immune checkpoint therapy enters the picture so what is immune checkpoint therapy I have to talk about immunology just a little bit here so in order for the t-cells to be activated for tumor cell killing it needs two sets of signals between the antigen presenting cells and the t-cells the first set of signal is delivered by the interaction between this t-cell receptor and the tumor antigens bond to an MHC molecule the second set of signal is provided by CD28 binding to B7 so in the way this is like driving a car okay so the first set of signal is like the ignition system so you need to turn on the car and then the second set of signal is like the gas pedal after turning on the car you need the gas pedal to speed up the car so that you know you can kill tumor cells however we all know if we only have the ignition system under the gas pedal and then you drive our car sooner or later you are going to run into problem because you are going to speed up and then you cannot slow down and then you are going to crash and burn so the immune system is actually very smart it actually has its own braking system one of these brakes is called CTLF4 the other one is called PD1 they are responsible for slowing down the immune system after it's activated however the side effect of these brakes would be decreased tumor cell killing so James Ellison who is the director of the immunotherapy platform at MD Anderson found that if you use an antibody to block this inhibitory to block these brakes to take the brakes off these t-cells you actually can allow the t-cells to stay activated for augmented tumor cell killing and that's that's how the first drug epilumina is developed so epilumina is basically a monoclonal antibody against that molecule named CTLF4 here it was first tested in advanced melanoma patients who on average has a survival of about a year just like metastatic kidney cancer however as you can see from the data here after these patients receive epilumina over 20% of them can live up to almost five years and that is quite significant so what if you put epilumina and the other antibody that breaks anti-PD1 which is named Nivellumina so again this is in melanoma patients as you can tell from the data here so on average please remember on average these patients live for about 12 months but here at one year 82% of the patients are still alive by three years over 70% of the patients are still alive and then that is very very dramatic and that's why immune checkpoint therapy was offered breakthrough of the year on by the science magazine so what about this therapies in kidney cancer so based upon this first two trials at lower concentration epilumina didn't have very much effect in kidney cancer however at the normal concentration that we use for the treatment of metastatic melanoma patients five out of 40 patients actually had partial response for Nivellumina the result is even better so at six months over about 20 about 24% of the patients actually showed partial response and the 24 patient 24% of patients actually showed stable disease so overall almost 50% of patients actually benefited from Nivellumina at a very low concentration of one milligram per kg per kg at a higher concentration the response rate increased to over 30% and the stable disease rate increased to over 30% so overall more than 60% patients actually benefit from Nivellumina so what about putting those two drugs together we don't have data yet recently we just designed a clinical trial to combine either Nivellumina with epilumina or bevacizumina which is a standard treatment for kidney cancer as discussed by Dr. Tenir so we designed this three-arm trial that in the first arm patients will receive Nivellumina in the second arm patients will receive Nivellumina plus bevacizumina and in the third arm patients will receive the combination of Nivellumina plus epilumina after six weeks of treatment they will have surgery to remove the kidney with disease and if they have either stable disease or response before the surgery they will continue on Nivellumina so this trial actually has quite a few advantages first of all all these patients will receive at least double therapy or even triple therapy so patients in arm one will get Nivellumina plus surgery which is a standard treatment for metastatic disease with the intact kidney tumor so patients in arm b and arm three will receive triple therapy second of all this design will allow us to collect blood samples before and after each trial and also collect tumor samples before and after each treatment this way we can study the biology of these drugs directly in human body and hopefully we can identify biomarkers to improve these therapies and also identify new targets for further therapy so with this target agents we know we can prove prolonged survival a little bit and with immunotherapy we can see this tail end effect which is long-term survival and by combining this immunotherapy agents with each other and also with the traditional target agents we hope we can not only prolong survival but also increase the response rates in patients with metastatic kidney cancer with that I would like to thank the collaborators from the immunotherapy platform from pathology on geo-oncology and also urology but above all I would like to thank our patients and their families for your support with our research and clinical trials and we hope and I hope we can continue to work together to rewrite cancer history thank you very much for your attention all right thanks JJ our next speaker is Dr. Brian Chapin who's a member of our urology faculty and he's going to talk to us about the role of surgery and the treatment of patients with metastatic kidney cancer good morning I want to thank Dr. Wood and the KCA for inviting me to speak as Dr. Wood mentioned I'm going to be speaking about the role of surgery in the setting of metastatic kidney cancer to include a pseudo-reductive nephrectomy which is removing the kidney and metastasectomy which is removing metastatic sites I have no financial disclosures so we've already heard today by many of the speakers that metastatic kidney cancer has many challenges it's not responsive to most traditional toxic chemotherapies it's not responsive to radiation therapy the minority respond to cytokine or the traditional immunotherapy and we have rare complete responses with targeted therapies we've seen something similar to this with Dr. Gauss presentation on the timeline of kidney cancer therapies from cancer therapies from active surgery in the treatment of kidney cancer back in the 1960s to the adoption of immunotherapy and the treatment of patients with advanced and metastatic kidney cancer to the advent of targeted therapy with seraphim in 2005 now on to even some newer targeted therapies and as well as immunotherapies and vaccinations that are coming available so we know that we have all these medical therapies the immunotherapies and the targeted therapies so the surgical therapies that can be incorporated into this are pseudo-reductive nephrectomy and metastasectomy and really the question of sequence or therapeutic sequence when do we do these surgical maneuvers in order to try to optimize patients outcome and the standard currently would be pseudo-reductive nephrectomy systemic treatment and possible metastasectomy but many options exist so for some of you I wanted to define some of this some of the newcomers here what is metastatic disease and I have this discussion with my patients a lot in clinic metastatic disease is spread of disease to a site other than the primary site so in the picture here you can see a tumor in the kidney here the tumor can spread typically through two directions one through the blood vessels or hematogen to spread so it travels through the blood and it ends up in another site and then a tumor grows at that other site or lymphatic spreads so here's a depiction of a tumor with tumor spreading to the lymph nodes that are nearby pseudo-reductive nephrectomy is the surgical removal of the kidney in the setting of known metastatic disease and metastasectomy is removal of a sighted disease that is spread from the primary to another site within the body and it's still kidney cancer even though it's at another site and a lot of people will make that make that mistake when they're trying to understand what we're talking about I also you've heard a lot of discussions today about different trials about different studies about things that without having the background you may not realize why it's so important when we describe these studies randomized prospective studies are our gold standard those are the clinical trials that we've basically followed similar groups of people over a period of time after an intervention the intervention may be a new drug it may be a surgical therapy half of the group may get that intervention while the other half gets a standard treatment and therefore we can actually actually effectively compare the two and see which is the better outcome randomized studies are what make standard of care retrospective studies are studies when we look back at events that have already occurred so patients received the therapy because their clinician felt that that was an appropriate therapy for them and then we look back and say okay of those who received the therapy compared to those that did not what were the outcomes so as you can imagine that's open to significant selection bias where if a physician feels that the patient may benefit obviously they're selecting those patients out so those those are mainly hypothesis generating studies that help us to develop clinical trials but they're not things that we should be practicing standards off of and the other thing that came up today a lot is Kaplan-Meier curves and some people may not even know what the Kaplan-Meier curve is so I figured I would include this just so you can get a sense of what we keep talking about when we're talking about significant differences in these trials so Kaplan-Meier curves is is simply just a measurement of the fractions of patients alive for a certain amount of time after a treatment so at time zero the treatment is applied you have two groups of or two populations of patients they receive different therapies they may have something in common but something will be different between the two and then you look at the outcomes over the period of time and you say okay arm a is clearly has more patients alive than arm b so it makes sense that that therapy may be better and the reason I tell you that is because I'm going to show you some Kaplan-Meier curves and I want you to see that sometimes these differences are very significant meaning a wide split between the curves and sometimes they're not so significant and that's what raises the questions that that that follow so cytoreductive nephrectomy in the area of immunotherapies was was this was one cytoreductive nephrectomy was first evaluated and this is in two publications from 2001 these were randomized prospective studies so the gold standard which looked at immunotherapy with removal of the kidney versus immunotherapy alone so these are two trials both of them the dotted line on the on the left side and the solid line on the right side are the arm of the trial that had surgery plus immunotherapy the bottom lines are the one that had immunotherapy alone so these are not pre-selected patients these are randomly assigned patients and there's a separation of the curves which would indicate that the patients who had the nephrectomy in addition to the immunotherapy had a better outcome hence cytoreductive nephrectomy became part of the standard of care in the treatment of patients with metastatic disease so in the current era now with all of the newer systemic therapies since 2005 in again with the advent of seraphim in 2005 being approved we see even improved responses both in the kidney and in the metastatic sites with these targeted agents and the question became does cytoreductive nephrectomy still benefit or still provide benefit to patients in this era and then if it does what sequence of therapy should we should we undertake and then can we identify those who actually would benefit most from surgery so you've seen a lot of the kind of these graphs and these depictions and these illustrations of trials and the point is for the carmena trial this is asking the question is nephrectomy or cytoreductive nephrectomy still relevant in the era of targeted therapy in this case being synitinine and what this all this really basically says is does targeted therapy with or without cytoreductive nephrectomy make a difference and so the groups are randomized and split into the those that receive surgery followed by the drug versus the drug alone the outcomes of this should will hopefully be available at some point in the future but are not available at this time another study and and from what some of us would believe is probably the more important study is the seratime trial which again really just evaluates the sequencing of targeted therapy with cytoreductive nephrectomy so this looks at all patients receive nephrectomy it's whether or not they have the targeted drug or the systemic drug up front or after the surgery is completed and so the question becomes while these trials are accruing patients and rolling patients and we're analyzing the data and waiting for the outcomes what do we do and so this is again now this is retrospective data so this is so what has happened already in the past five or seven years in patients in this era and what what does that tell us and these are patients that were selected for tend to go nephrectomy in the setting of having not received immunotherapy but being on soon it nib is what she's one of the targeted agents and then looking at and comparing those to patients who did not undergo nephrectomy so the top line of the green line is patients who had the nephrectomy and the blue line is the ones that did not have the nephrectomy and the green line patients are living longer in a larger portion of them but again selection bias plays into this and it's difficult because are the patients with the blue line not given surgery because they were not offered it at the time or is it because they were not offered it because they were not necessarily candidates for an operation similarly by the paper by Tawari et al from 2011 we're looking at patients again who had targeted therapy whether or not they had their kidney taken out so the red line is yes kidney removed black lines no kidney not removed the red line did better patients did better if they had their kidney out the difficulty here again is the selection bias and as I mentioned this what is the selection bias in this case these patients the groups were different and they differed in age they differed in performance status they differed in the number of metastatic sites and they differed in number of calcium levels which is one of the things we look at when we measure someone's prognostic level and on the right of the screen you can see the these again the Kaplan-Meier curves and these are separated out looking just to people with good performing status versus poor performing status and really they didn't seem to be a benefit in those with poor performance status so it's difficult to really interpret this but at least it gives us some idea that if patients are surgical candidates it's possible that they'll benefit still from removing the kidney in the setting of targeted therapy moving on to metastasectomy so the difficulty with metastasectomy and this is a conversation I've had with with my colleagues is there really there's no randomized trials looking at metastasectomy so removing a site of disease whether it's a solitary site of metastases multiple sites of metastases after the kidney's been taken care of or even with the kidney in site 2 there's no randomized trials so what we have is data on patients that had sites removed and their outcomes and then we're supposed to interpret from that whether or not it's an appropriate therapy the goal of metastasectomy is to be clinically free of all sites of disease the benefit if you can actually remove all sites of disease and in fact patients can be essentially cured of their disease that would be ideal but also it allows for a period of time where patients may avoid the need for systemic drugs or systemic therapy if you can tell someone who thinks they're going to require systemic therapy for the rest remainder of their life that they can be off drugs for a period of time if they have an operation it may be something that that would be worthwhile we do know that there's improved survival when all disease is removed compared to when all disease is not removed we know that survival is related to the site of metastasis so some sites if you've removed tumor do better than other the we also we what we don't really know is the relationship between systemic therapy now and metastasectomy and again sequencing issues of when we should be applying these therapies these are a number of studies that have been completed again in a retrospective manner looking at the outcome of patients who underwent metastasectomy the numbers are not meant to overwhelm you basically what it says is patients who have resection do better the question is why do they do better looking at specific metastatic sites we know single sites are better than multiple resectable is better than unresectable there are many sites that kidney cancer goes to some of the more common ones or ones at least that have been studied are brain thyroid lung liver bone retroperitoneum and adrenal looking at lung this is an example of someone with lung metastases there are many studies looking at patients specifically in the again in a retrospective manner who've had lung metastases excised and what we can say is that resection of lung only metastases if you can remove all of the metastases those patients do well 74 cancer specific survival means they don't die of their disease incomplete the patients that couldn't have all their disease removed had a 19% cancer specific survival so far worse than if you can do it so if you're going to do it and you can do it all great if you can't take it all out you may want to reconsider the predictors of good outcome are completeness of resection the disease free interval so that if they're disease free for longer than two years it's more likely that they're gonna have a better outcome the absence of lymph nodes in the chest and then the smaller number of metastases at the at the time of diagnosis I include liver as a discussion here point just because that you know with lung it makes sense to do it based on the data that we have available with liver it's questionable and I'll explain why patients with liver metastases tend to do poorer than patients that don't have liver metastases this is a small study but it's one of two studies that are available 17 patients with solitary liver metastases 11 of them underwent complete resection four of them died in the post-operative period so perioperative mortality is relatively high for this group their mean survival over the the course of all of them were 16 months which is lower than what we've described in some of the others and then we know the poor outcomes are in patients with larger tumors and also those who have impaired function of their liver as a result of their tumor so now what about again the same question what side of reductive nephrectomy is what do we do as far as metastasectomy now that we have these better drugs that respond the tumors respond better to in the immunotherapy era let me take a step back in the immunotherapy era we do have some data on patients that had immunotherapy followed by metastasectomy and this is an md Anderson study that was done by Dr. Daliani and colleagues 38 patients received immunotherapy those that did not have progressive disease and no progression at all underwent metastasectomy of the ones that ended up having surgery 21 had partial or complete responses we've thrown those words out a lot today too but basically those are the ones that had some response 76 had stable disease so considered non-progression after 76 of these patients could undergo a complete resection so they were considered no evidence of disease after the resection 90 percent of them went on to receive additional systemic therapy after surgery the median time to progression so the time to when they first had identifiable disease with 1.8 years the median survival was 4.7 years and again back to the receptability 5.6 years if it's completely resected 1.4 years if incomplete the resected the predictors of good outcome were having no evidence of disease or any D after surgery or pulmonary metastases and then the question is asked by dr. Karam who spoke earlier is just what about in the air of targeted therapy what if we do targeted therapy followed by metastasectomy and this is a obviously a more recent study because the targeted therapy becoming available in 2004 2005 this was 22 patients again a retrospective evaluation of these patients targeted therapy was given and then there's their metastatic site was removed lots of different sites were looked at retroperitone and being the most common which is where the kidney lives normally of these patients 50 percent 11 out of the 22 had a recurrence of the ones that recurred the median survival was was poor 10 months in at the end of the the follow up 21 patients were still alive the median survival was 25 months for that entire group and this is I think the key point is that the median time off of the therapy so basically a period of free of having to take drug was 13 months his study showed it's feasible to do this but really it needs further study and in a prospective manner is the gold standard to try to to show whether or not this is effective and how we can benefit patients most by using it the take home messages for the talk today I think is that surgery is still an important part of the treatment for metastatic kidney cancer the benefits achieved are best in patients that have good performance status good surgical candidates have limited metastatic burden have long disease free intervals in between identification of metastatic disease patients that need palliation for pain and and and discomfort and is ideal when complete resection is feasible we need to better identify patients better identify who would bet who is going to provide who's going to receive the most benefit from this as you heard about Dr. Wood's talk on neoadjuvant therapies and his attempts to try to to select patients that are better candidates for for surgical therapy and then clearly we need to study the integration of this with the systemic treatments both targeted in immunotherapy given what we just heard from Dr. Gow I want to say thank you and it was a pleasure to be here it's always a pleasure to welcome Tom Hudson he's been sort of a mainstay force at these conferences over through the years he flies down from Dallas in the morning and flies back in the afternoon so we've asked him to give us a lecture on sort of the future of kidney cancer what are the most exciting therapies that are on the horizon that might be realized by many patients that are here in this room Tom thank you Chris and and I'd like to thank the KCA for their continuing support and since we are a few minutes ahead of time actually I think about 15 minutes I guess it gives me a longer period to talk Chris right no just joking but anyway we had excellent talks I got a chance to listen to I think 90% of the program today and my colleagues sitting up here Dr. Taneer had done a great job and provided an overview of the TKI's and actually in the immune based therapies some of the novel agents that we're going to discuss briefly have already been covered so I think as my high school teachers used to say repetition is always good because it helps drive in the message since we are a little bit ahead of time I'd like to just take a moment and say that being the outlying speaker today because everyone else has been based here at MD Anderson it gives me the opportunity to say that that globally and nationally the RCC community of doctors is quite strong very friendly and we share and work together at a level that a lot of our other peers and other tumor types and other scientists don't have so we have great relationships both personal relationships and academic relationships so it's a very tight community so hopefully that gives patients a lot of comfort in knowing that the doctors are not fighting each other that we actually are on the same team to try to cure this disease and so these doctors you've heard today I get to the chance to interact with at national and international venues the kidney cancer association has been a pinnacle for us in the kidney cancer world and have been vested in new therapies for kidney cancer back when kidney cancer was not sexy back when all we had was interferon or interleukin 2 for therapy so it's great to be here to talk about promising new therapies my agenda is is simple I want to be since I am the last didactic presentation today for you I wanted to provide an overview of the current status of systemic therapy you've heard the details of the clinical trials by Dr. Taneer talk a little bit about the new trials and some of the clinical trial methods that we're doing you've heard that mentioned briefly by Dr. Taneer some of the innovative patient preference trials and then also talk about some new targets and ongoing trials in kidney cancer so let's just start off here this is a very busy slide don't worry about the numbers this is just to show you we've got lots of drugs you've heard that we've got seven new therapies available for this disease and one of the benefits probably one of the few benefits of having multiple therapies is that we've got choice one of the negatives is that we need to have data and we need to have experience to help guide us on the choice and I think a lot of us have felt in kidney cancer that the rapid development of new drugs in the disease has somewhat outpaced us scientifically in knowing how to best utilize the drugs we have and so one of the new things moving forward for us in kidney cancer research is going to be trying new trial designs that allow us to compare because you as a patient and me as a doctor I want to know which drug compared to the other drug is better and we've got to do those type of trials so it's one thing to have a bunch of drugs on the market but do we really know what is the best sequence of the drugs um are there you know do we really fully understand the combinations of the drugs and that is something that's going to take years here for us to discover but what is clear is that we have of these panoply of drugs when a patient comes in to see us and they need to start their therapy for metastatic disease we generally have across the world two drugs that are chosen and those drugs are synidinib and posopenib those are the two most commonly prescribed agents in the first line setting for this disease synidinib and posopenib and so we've actually done something that we've done across other tumor types too is we've come up with these treatment guidelines so it's one thing to have an expert like Dr. Taneer say okay you're going to get posopenib as frontline therapy but what is Dr. Jones who's out in you know middle of nowhere Texas what is what what data source does he have and so sometimes in the patient may not be able to drive to see Dr. Taneer or they may not be able to drive to see me in Dallas well the guideline serve as a reference point for doctors to to know what experts feel would be appropriate therapy and what I've shown here is to be not politically correct because I didn't choose the US guidelines I chose the European guidelines these are the ESMO guidelines 2012 but they're somewhat similar to what we have we use something called NCC and treatment guidelines and the first thing to mention a guideline is not an absolute it just gives you an idea because we recognize patients are individuals and we need to tailor the therapy for the individual patient but as you can see in the first line setting synidinib or posopenib posopenib has a little asterisk there those are the two most commonly utilized which drug you get the trials show us and we'll review that briefly it really doesn't matter in regards to the outcome of response there's a little bit of difference in side effects so a doctor chooses one or the other and I said globally that's well those are the two that are used and if you have very poor features on your tumor the way it's behaving which is extremely rare about 10 percent of patients we see are what we consider poor risk they have advanced symptoms the intense surlimus is pretty much the global standard for that setting so how do we select we select therapy based upon the the individual drug the differences in uniqueness between the drug in regards to side effects that the clinical trials have shown us we look at patient specific factors there's no patient that's the same as the other so patients have their own unique tumor burdens they have their own medical histories some patients come in with histories of heart failure heart attacks strokes other things that make us choose agents differently we try to apply the available data that exists the global data on on therapy for the disease and we do this to try to get the optimal efficacy we want to choose the right drug for the right patient that's going to give us the best outcome and so there's a bunch of factors here which we've actually spent time in the pharmaceutical companies obviously they spend time maybe sometimes for different reasons they want to know why we choose what we choose and why patients choose what they choose when it comes to these different therapies and you can see listed here are the different patient factors that go into it and the different agent factors that go into it but without a doubt when we survey both doctors and we survey patients and people respond you know when when people respond truthfully the biggest factor that guides both the patient and the doctor and their choice of therapy when they're familiar with the data is efficacy so patients want this is to start off as initial therapy their first line of therapy they want the drug that works the best okay they're not as concerned about the side effects if they have a drug that works better and and shrinks the tumor more so that is something important for us to know as we're selecting these agents another field of research is trying to find are there ways that we can predict before we give the agent to a patient who is going to respond to the agent wouldn't that be great wouldn't it be great to be able to take your tumor Dr. Wood or Dr. Karam cuts out of you to send it for genetic analysis and then we find out we get a print off report Dr. Taneer gets a print off and says this person is going to get pysopinobotrant and they're going to have an 85 likelihood of response or a 90 percent likelihood of response wouldn't that be great you could hand that to your patient that's the future I think everyone in this room knows that we are doing genetic analyses now of tumors and it's not going to be much longer you know I'm hopeful that in my lifetime for sure that I would be able to see be able to do that and that's the hope for cancer is to individualize therapy to that degree so you know I've told you started off that we have seven of these drugs and we have to commend pharmaceutical companies for doing something that's tough for them to do and that is to risk it all where they actually take on another drug and so that's what happened in the compares trial that Dr. Taneer mentioned to you there was the two most commonly used drugs globally are synidinib and pysopinib and we have a trial which can be faulted now we and our academic lectures you know in our meetings we we kind of ripped the trials apart and and they're not there's no perfect trial but this was a trial that was designed to show that pysopinib was as good as not worse than synidinib wasn't designed to show that it was better it was just to show that it was similar or equivalent to and that was this particular trial what you see here is overlapping curves I mean it doesn't take a scientist to know that these drugs are pretty similar in their activity so that allows us Dr. Taneer and myself to say either drug is probably going to be okay for you either drug is going to give you the same likelihood of response but what Dr. Taneer said is that these drugs are a little different even though they hit the same targets they they they do so in different ways and with that comes different side effects and there are certain side effects the ones that are in the teal color up here that are favoring synidinib and there are a group of side effects that favor pysopinib and as you can see as I started off every patient's different you could imagine there may be patients that are going to do better with one drug over the other based upon these type of side effects and so this is what we as doctors utilize when we're choosing agents another kind of this is the when I was mentioning that I wanted to talk about novel trial designs this is it this is the first time I'm aware in cancer where we've done a patient preference study now again academically in behind closed doors scientists will argue about the validity of these trials but certainly it was from a patient's perspective this was a home run because it was an it would allow patients to have a voice to do a trial where a patient could actually vote in the as part of the trial results whether they liked one drug or another based upon side effects and that's important to know when we have drugs that are very similar in their activity if drug works about the same it's important to know which which one's better for the patient intolerance and so as Dr. Tanier mentioned I won't go through the details of the trial they looked at both the doctor's impression of benefit and they and side effects and they looked at the patients and we were able to show that actually the average person seems to favor pysopinib in regards to side effects better than synidinib so that important stuff to know and there was the breakdown that Dr. Tanier mentioned to you 70% preferring pysopinib 22% synidinib again with a lot of scrutiny on this trial this was not a perfect trial but at least it gives you an idea that there are differences between the drugs that's first line you know um what about second line well we recognize we're not curing anyone despite these unique cases and I have them in my own practice I have patients on frontline therapy synidinib and pysopinib for seven eight nine ten years I mean amazing lengths of time but that's not the average person we see the average person is going to have progression on one of these therapies at some point and then the decision is to move on to the next therapy and our goal as doctors is to give our patients all of as many options as many of the available agents as possible to hopefully get an additive benefit of prolonging survival as long as possible and what we are trying to figure out is what's outlined here contribution is each of these different therapies we give patients we're trying to understand how much each of those therapies add to the overall survival but our goal is the same give as many of the therapies as possible to our patients and I will tell my patients when I first meet them that that is our goal so that they understand that it's unrealistic to think that synidinib or pysopinib is going to be the only drug for them that's what we start off with and that we have all these other drugs that we are going to sequentially use to drive survival as long as possible and we've got all these drugs again to do this and two of the ones that have been most most punitively most commonly used as next drugs outside of a clinical trial with a caveat doctor you know md anerson baylor rymat we are big clinical trial centers so our patients are going on trials but for the average patient who's not on a clinical trial they're going to be getting one of these drugs next and whichever one they don't get next they get that one after so we sequentially use these drugs and the two most commonly globally used drugs now as second-line therapies are either the affinitor everolimus mTOR inhibitor or exidnib which as dr. tenir mentioned was the second generation powerful vegev inhibitor and so at the end of the day this is my this is finishes my review of what you've heard so far is our goal is we want to achieve long-term survival in that we recognize in 2014 is going to require careful selection of agents for each individual patient and i can tell you i can speak in general terms this is generally what i do first second third fourth line but that's a generality and it changes based upon individual patients it changes upon the individual patients response to the therapies so the way they respond to the first line therapy may influence my choice of therapy in the second line setting the side effects you can imagine when they have a side effect in the first line therapy that may influence my choice in the second line therapy etc so we do even though we make general statements about what how we're going to use the therapies we do want to tailor that to individual patients okay busy isn't this a nasty slide right tough slide um i borrowed some of my slides from tony terry who's one of our colleagues at harvard um so if he's watching on the on the videocast he'll recognize some of these slides um this slide very busy cartoon is depicting the sites of action um biochemically in the cancer uh cell in the microenvironment so we've got up here synidinib, seraphinib, posopenib, and exidinib which are predominantly working at the endothelial cell that's the cell that makes the vasculature and then we've got the mTOR inhibitors which are going to be working down here in the mTOR pathway well we recognize cancers are so complex i mean major complex phd level complex that there are a variety of other targets to potentially to hit to potentially affect kidney cancer growth and one of them that's been looked at here is in this red blocks is growth factor receptor for MET you hear about MET which is a growth factor receptor in FGFR fibroblast growth factor receptor those are two targets that novel drugs for kidney cancer have been studying and the first one to talk about is cabosantinib cabosantinib is a MET inhibitor it also inhibits VEGF and this drug cabosantinib has a brand name of Cometric and has received FDA approval for thyroid cancer already but our colleague Tony Twerly who's trained with me at Cleveland Clinic and is now heading the kidney cancer program at Dana-Farber and Harvard I did a trial and patients with refractory kidney cancer and including patients with a subtype of kidney cancer which doesn't do well with therapy a psychomatoid type of clear cell kidney cancer and he was able to show in a refractory setting so third fourth fifth line setting that there were good responses confirm partial responses of 28% on patients there was only 25 mind you in this smaller trial 52% of patients having stable disease in a median progression free that's the length of time the patients able to be on the therapy with control of over a year so an exciting drug and they included in this trial some different correlative studies and this was radiographic responses using volumetric scanning and just to show you this was the baseline of one of his patients on the trial and then after eight weeks of therapy showing dramatic response and this is in point because this particular patient you can see was a heavily pre-treated patient patient who's already had four lines of therapy they had synidinib they had a traditional chemotherapy drug called gem cytobine which is a chemo drug which is used in kidney cancer they had the mTOR inhibitor affinitor which is commonly used second or third line and they had this drug utenine might not recognize this ramyut serumab ramyut serumab I don't even know if I pronounce it right but it's it's an abastin or bevacizumab like drug it it targets VEGF receptor 2 antibody so this patient's been treated with drugs that should work in kidney cancer and they're getting this as a fifth line therapy showing this degree of response so obviously a lot of excitement was generated by this trial and so this has resulted in cabozantinib being studied in two major phase three trials and if these trials are positive the drug will move to FDA for regulatory approval these trials are ongoing as we speak in the cooperative group the alliance clgb cooperative group don't tell me why they come up with these names but that's a group of cancer centers generally through the midwest of the united states is doing a randomized phase two trial comparing the cabozantinib drug with upfront synidinib at the traditional schedule four weeks on two weeks off so this is going to be in a front line setting and then probably the big trial that will result in regulatory approval though is in the second line setting and that is the meteor trial and nizor are you doing this trial here yes there you guys have this available to you in houston i'm also doing it in dallas this is a major phase three trial this is the regulatory approval trial for cabozantinib versus everolimus and patients have had to have had progression after frontline vedgef targeted therapy the primary endpoint is progression free survival and secondary endpoints overall survival okay so that's exciting there as you've heard already there are different types of kidney cancer right so clear cell is the predominant type the one that we know the most about the second most common type is the papillary type and the papillary actually to be more sophisticated and more complicated there's actually two types there's a type one and a type two the type one hereditary papillary renal cell cancer is associated with a met abnormality met gene so just like vhl was a gene associated with clear cell met is a gene associated with papillary renal cell cancers and we have developed inhibitors that inhibit met so and met is involved in other cancer types too but in kidney cancers what we're interested in there was a drug ferretinib which is a dual inhibits vedgef receptor and inhibits met receptor was studied by our friend tony again in patients with papillary renal cell cancer showing significant evidence of benefit this is what we call a waterfall graft and so what's going down negative here is the amount of tumor shrinkage that's seen so you can see the majority of patients are having some degree of tumor shrinkage when they get this drug in their papillary renal cell cancer and it's a minority amount that actually has tumor growth and they showed a progression free survival of almost 10 months which is not bad in comparison to other drugs that we use for the disease so again an exciting new drug for pigeonhole for a rarer type of tumor papillary um what about biomarkers we talked that we don't have any predictor markers in the future there with maybe um genomic sequencing and and looking at the tumor but we're also looking at biomarkers we're looking at ways and chemicals that we can test that we could determine whether or not a patient's responding to a therapy in how long they'll respond and there's a variety that we've looked at unfortunately none of them have been validated yet but we continue to search for these these include things for interleukin 2 hyacinthus interleukin 2 trying to find ways we can predict and um who's going to benefit from that vedgef targeted therapy there's a list and mTOR inhibitors so this list and is continues to grow and is ongoing as i end now you know we've talked about i think cabozantinib which is probably uh most would agree is one of the major drugs that's on the horizon it's it's an oral drug um similar to that to sutent votrient family in regards to it being an oral drug with similar side effects but inhibits um cmet the ferretinib drug is is for a rarer indication the next big group that is really on the horizon is the immunotherapy you've heard about in detail so just briefly there's a couple vaccines that are being studied vaccines that are being studied in patients and the refractory setting in a vaccine types of therapies that are being studied in patients um as adjuvant therapy um and this is just a phase two study looking at one um this ima-901 which is has 10 tumor associated peptides and these tumor associated peptides are supposed to stimulate the immune system to fight the cancer and they were able to show and patients that actually develop immune responses to this peptide a significant benefit and and these were patients with advanced rcc who had prior therapy with both interferon interleukin 2 tkis which would be like the synidinib bisopenib and had documented progression that when they gave them this type of therapy and the patients had an immune response to it that they were able to have benefit um this has resulted in a phase three trial that i have not seen the results of yet um looking at this in combination with suthent so people say why would you take an immune stimulator and combine it with suthent well part of the story that you haven't heard about is that suthent itself besides inhibiting vegev and blocking blood vessel development is an immune modulator itself you know we haven't spent a lot we don't fully understand it well but it is clear in labs around the world that suthent can affect the way the body's immune system is responds to the cancer and so there's been a lot of immunologists that have worked on this um one of my mentors at the Cleveland Clinic um has um published on this and so the thought is that maybe you could use this stimulator of the immune system this pen 10 peptide vaccine if you will and combine it with suthent and hopefully um adjust the t-rex and the the tumor and make them more responsive there's another trial this is a um a autologous dendritic cell vaccine i don't know if you're doing this nizer i'm not you are so this is the adapt study that is a similar type of thing where you're combining um the the therapy sequencing it with suthent again for a lot for the same reasons that suthent does have immune modulatory effects on the immune cells the tumor associated immune cells and then finally as i and you've heard this eloquently mentioned already that the break on the immune system is this interaction between pd1 and pdl1 and you you know there's energy which is when you immune system is you know you're allergic you don't have reactions to normal immune stimuli or you on the other extreme you have autoimmunity and i'm sure you've heard of immune related diseases like rheumatoid arthritis sle stuff so there can be situations when your immune system just attacks everything so you know the problem with the pd1 pdl1 is that's the break and so we're trying to design therapies that will take off the break that the cancer puts on the immune system to take it off so that the immune system can work but at the same point not throw someone into autoimmunity where they're having the immune system attack the body because that produces bad side effects that would be similar what happens in bone marrow transplant patients and so there's been a lot of work into this their pd1 inhibitors and the pdl1 inhibitors these are them shown here on the slide from earlier studies this again is from my friend tony's presentation at 2013 asco meeting you can see with the nivola map which is the bms compound that there's this is a spider graft and again anything going down negative here is a response it's the degree of tumor shrinkage you can see the majority of patients that got this pd1 inhibitor this this checkpoint inhibitor they were having benefit with tumor shrinkage with kidney cancer and then you can see one of the pdl1s also about 50 of them having some response to the therapy so both of these antibodies to those checkpoints that are the breaks of the immune system are demonstrating benefit one of the interesting things is that we can actually test the tumor for expression of pd1 pdl1 and so when they look at pdl1 the problem is it's not perfect it's like PSA testing it's not perfect so it's unclear whether this will be useful for us but but clearly if a tumor is expressing pdl1 those are the people that are getting their responses to a pdl1 inhibitor versus if you don't express the pdl1 you're not so you remember what i initially said when i started the talk the future would be able to do a test like this on someone's tumor and determine who is going to benefit from the therapy and who is not before you give the patient all the side effects of the therapy and so this is a step in the right direction again but it's not perfect it's unclear whether this will move forward and then there are there's several phase two trials of nivolumab this is an ongoing trial phase three trial it's on the verge of closing soon it closed already i thought it closed in decemberish time period december january but the results will be forthcoming within the next calendar year most likely of nivolumab versus everolimus as a second line therapy or third line therapy so patients could have had one or two prior vegeth therapies and get this as a second or third line so whenever you see phase three trials like this will you have the the experimental drug comparing it to one of the standard drugs that should tell you that that is a registrational pathway and if they beat it if they win they potentially can get the drug approved so that's what the nivolumab the pd1 inhibitor the pdl1 inhibitor which is the roast product we actually have um open i don't know if you all do but it's a front line trial and it combines the pdl1 with bevacizumab that's one arm versus sutent the other arm as a front line therapy and it's a phase three trial of that particular agent that that trials ongoing so you can see so summarize we've got cabozantinib which is uh phase three trials ongoing which is you know a very exciting drug that has high hopes that will become approved and on the market then you got these two agents the nivolumab phase three trial already completed waiting results and you got the upfront which i can't pronounce the name of that particular drug it's the roast pdl1 antibody which is ongoing so again three new drugs which have real hopes in the next year or two to hit the market so as i end i think i'm up with time chris is standing there thank you thank patients thank the kca thanks for your attention to wrap up the didactic portion of this none of this would be possible without the support of the kidney cancer association and i often find that patients are not aware of this incredibly valuable resource so we've invited kary kanoski to come and tell us a little bit more about what the kidney cancer association does kary hi so my name is kary kanoski and i'm the vice president of development and public affairs for the kidney cancer association and as dr wood mentioned um that you know sometimes as we're organizing these meetings we forget that a lot of you are new you know newly diagnosed and don't know a lot about what our organization does and how we might be able to help you so first the association we are an international not-for-profit organization and we have patients family members friends physicians nurses and other healthcare professionals that are part of our organization the mission of the association even though it's kind of long up there is pretty simple is to eradicate this disease be that the pain and suffering that the patients and their families both experience through this diagnosis the mission is focused into three areas education research and advocacy and i'll just talk a little bit about each of those specific areas but first for those of you that might not know much about the association as we were founded in 1990 by Eugene Schoenfeld um Eugene was a professor at the medial school of journalism at northwestern and was diagnosed with kidney cancer and at the time in 1990 there were no meetings like this there wasn't really much of an internet there wasn't really anything that gene could do to learn more about his disease there were no treatments and so he you know this wasn't acceptable to him he didn't want to just be diagnosed and go home and leave it at that and give up so he talked to his doctor and his doctor challenged him to do something about it so gene stopped stopped working and his wife you know was willing to support him and this organization and get it started and he took a few other patients and a couple physicians sat around his kitchen table and said what can we do so gene had message boards online before you know people were really utilizing those and he took a few people around the kitchen table to an organization today that serves over 100,000 patients and families and more than 102 countries and I think he'd be pretty amazed to see as we mentioned this morning that we're here at about our eighth or ninth meeting for patients and families here at MD Anderson in terms of education we provide support for both patients and for physicians so in addition to meetings such as this that are about you know a day to a half day meeting we do small support group meetings throughout the U.S. so if they're you know check on our website we've got an events page that will let you know if there's a meeting in your region and if there's not there's an email link that will take you to someone from our office that can help you get something started in your area so it can be something as simple as monthly every couple of months for for patients and their families to get together and you can have a speaker or just talk about you know kind of things that you're struggling with or you know positive things that are going on that treatments that might be working we also have webinars and videos available from the website and if you go to kidneycancer.org usually right in the front and center they'll be the newest video that will take you to our youtube page where you'll see a listing of videos from meetings like this we have one-on-one interviews with different physicians talking about trials that they might be working on and each of the members of our nurse advisory board has also done a short video to talk about the different therapies and side effects that you might experience for physicians we hold two large symposia each year one in the united states in the fall and then one in a different european city every spring so in a few weeks we'll be going to Dublin where we expect about seven to eight hundred doctors from all over the world to come and talk about you know some of the therapies the trials that you learned about today and some things that are still in early phases and you know what we hope to see in the future as i mentioned kidneycancer.org is probably the best place to go when you have a question be it newly diagnosed you hear something new from your doctor and want to learn more about it we try to keep the site up to date on a regular basis so there's always some new news right on the front page that'll take you to articles that you might have heard about clinical trials that you might want to learn more about we've also got a can't see it on there but where it says leave a message is usually that'll pop up and it'll be a chance to do an instant chat with usually myself or bill bro or always online so if you can't find something on the website or want us to help direct you somewhere just pop your question into the chat box and we'll be able to help you with that as i mentioned we do have some resources for clinical trials i think you've learned a little bit about some of the ones that are going on now but we do have a link to the national database and a matching service provided by emerging med so these will help you you know you can put in some information about yourself what therapies you might have been on the emerging med site will have somebody that you can call and they can help help direct you to a trial that might be right for you and then we've also got educational materials just to help better explain what a clinical trial is why it's important to participate in one that's one thing that we find is a lot of patients will contact our organization and say well i keep hearing about this but i don't really know what that means and when i have all these drugs that are available why would i want to go on a clinical trial so we've got a few videos that are new now that talk to you a little bit more about that in addition our publication we have kidney cancer some of you may have had an opportunity to read this if you contact our organization you will be able to order a copy or you can download a pdf or if you have a kindle there's we have an application for we have kidney cancer and its companion piece survivor stories about two and a half years ago one of our board members who's a kidney cancer patient thought that you know we've got all this valuable educational material with we have kidney cancer but we're kind of missing the personal stories and you know there's everybody's got their own story some just having surgery and you know no metastatic disease patients who've lived for more than 20 years going from from trial to trial and therapy to therapy and so he thought it was important to share those stories so we have a few um few patient stories and then many of them have their caregiver another loved one that kind of talks about that aspect of dealing with kidney cancer so if you haven't read either of those i would encourage you to visit the website and download a copy of either and then in terms of social media which we have seen grow um i should go back and look at my videos from this meeting every year because it seems like every time i come it's 20 000 more patients signing on to facebook and it's amazing how much that's grown i think we're over about 90 000 on our main kidney cancer facebook page now but every day you can talk to patients and family members from all over the world you know people want to tell their stories many times it's someone who's newly diagnosed and is looking for you know looking for help doesn't know where to turn once to hear other people's experiences on the same for our twitter page and then our two video channels youtube and vimeo um where you can go and visit some of the videos that i mentioned earlier about clinical trials past meetings such as this and the medical symposia while they're four physicians and healthcare providers only we do record the video of those meetings so that you're able to go and see the kinds of discussions that are had at that meeting and so with that i thank you all i hope that you've enjoyed your day and learned a lot and if at any time you have any questions you know don't hesitate to contact us just one reminder to that you will be receiving a link to a survey probably today or tomorrow just to get some feedback from this meeting so that we can continue to improve every year and make sure we're providing the information that you want so thank you again my homies all right can i have the uh the my esteemed colleagues um up here for the panel esteemed in quotations dr prom would you join us dr hudson dr gound shape him look i don't want to sit in the first seat who's that from a team that's dr hudson that's dr hudson seat i want to share with you don't smack me all right so this is uh another fun part of the of this conference i you know we do these all the time professionally where we call them tumor boards we're basically difficult or challenging or interesting cases are presented and you get sort of an opinion a wide variety of opinions about what to do and i think it's helpful for patients and families to understand that you know medicine is an art not a science and you know there is many times no right answer but uh it oftentimes is helpful to listen to you know the physicians going through a process of decision making uh as they are learning the facts of a case and helps you to better understand you know sort of where our minds are at the time uh so i have a series of cases to present we'll take a little break somewhere in the middle to go out and get the lunches and come back in and then finish up the the program with some cases um we have a steam panel of medical oncology and uh urology here like to remind my colleagues that we don't need to know what we could do we want to know what you would do try to keep your answers succinct and short as are um and we'll go from there all right so here's the first case so this is a 79 year old white female who presents with right sided abdominal pain she actually had cholecystitis at the time she presented and she went on to have a laparoscopic cholecystectomy uh which is gallbladder surgery for the uninitiated and she also was noted to have an incidental right renal mass she has a past medical history significant for hypertension hyperlipidemia hepatitis B and um arthritis she's previously had the cholecystectomy as well as a hysterectomy CT of the chest is negative and her labs are all within normal limits so you can see her films here she's obviously also had back surgery she's got some instrumentation in her back so just to show the audience uh you know all this this uh shiny stuff is metal present in the ladies back and it causes artifact on CT sometimes obscuring things and she's got this mass present in her right kidney right here this is another view on just the different phase of the CT scan where they let the die circulate a bit longer and you can see she's got this mass measuring probably about three to three and a half centimeters uh in the lateral aspect of the left kidney it extends down into the central part of the kidney at least to pierce that contact with the renal sinus and the collecting system here and she has a normal uh contralateral kidney as I said her labs are all within normal limits including her renal function so Dr. Karam how would you like to manage this patient all the options and I know you don't want me to say what all the options are so if you say them briefly you can so active surveillance is an option but I wouldn't recommend it given the size of the mass being more than three ablation I would not recommend since that mass is quite deep into the kidney the main options I think here are partial nephrectomy or complete nephrectomy if the patient's healthy enough I would recommend a partial nephrectomy but radical nephrectomy is definitely not the wrong thing to do as well but if she wants radical I would biopsy her first she wants what you want Dr. Karam what do you want partial nephrectomy okay would you do it through a robotic approach or would you do it through an open approach uh robotic you would do it robotically interesting okay yes um Dr. Mateen thank you for joining us this is a uh this is a 79 year old white female who presented with abdominal pain some past she's got some comorbidities previous surgery CT negative CT the chest is negative and she's got that right sided renal mass what would be your approach in this patient uh what was her kidney function normal labs are within normal limits her GFR is probably around 75 okay I give her the option of her laparoscopic radical versus uh um we do a robotic partial the only thing I'm a little bit it's a little interesting looking is that I can't really point but there's a part of it that at least on the other films looks like it's invading in the collecting system or in a vein or is that just artifact can't tell uh it's not it's not invading into the vein although it does have it does have contact with the collecting system for sure yeah so there's you know there's trade-offs with both those procedures she's going to lose significant renal function by removal of the whole kidney the partial on the other hand would be associated with somewhat higher uh complication risk so what do you want to do doc um if she was she left it up to me I would do a partial okay and you and you would do it robotically yeah um Dr. Chapin any role for neo-adjuvant therapy here okay that's the thing how would you manage this patient I would I would offer a partial as well but I actually would do this one open I wouldn't do this robotically and she did go on to receive an open partial nephrectomy and it was a stage t1a clear cell and her post-op of course was unremarkable so any would anybody do a biopsy ahead of time only if I'm planning to do a radical nephrectomy so explain the logic of that or active surveillance just I would hate for someone to lose their kidney for a three centimeter mass that could be benign so if you're going to do a radical nephrectomy you would do a biopsy to prove for a small mass yes if I'm going to do a partial nephrectomy there's no reason to do a biopsy because I know the rest of the kidney is still going to be there and if the biopsy came back as benign you would observe or I would not go for the radical I'd change it and do a partial if that was the second option huh what if it's you know you know sometimes the biopsy doesn't always say benign benign sometimes it's inconclusive or oncocytic so you know observation or surveillance would be more of an option at that time as well but if the patient is having symptoms such as hematuria like you said this is very close to the urinary system there on the second picture on the right it might be an option to still do a partial nephrectomy I think it's an issue you know it's it's unconventional we don't think about doing partial to decide to do a radical I mean to do a biopsy when you're considering a radical but I think the logic of it actually makes sense and it may not have 10 years ago when we weren't able to distinguish benign from malignant quite as well but I I kind of buy that argument what about the argument that if it's active if we're going to do active surveillance we should do a biopsy do you agree with that I do you know I I've become I used to leave it very optional for patients it's still optional but I do encourage it I think most patients want to know if they have cancer or if they don't and it also puts them in a position of power when we're observing it and it does something that is unexpected and that's not a not infrequent so it may shrink it may get bigger but then you're in a position of more power as a patient I think when you kind of know what it is so that is an unusual perspective for a urologist most of them would not biopsy or be I don't know what would the other guys do show the hands who would biopsy for active surveillance and who would not so who would biopsy not everybody okay dr crumb what's your selection criteria so if I you know we have some patients let's say if a patient's 85 year old and has a one centimeter mass realistically whatever that biopsy is going to show we probably won't be doing anything so unless a biopsy is going to change something that I'm going to do I would not obtain a biopsy now if a patient says I will not do surveillance unless I have a biopsy it's a different story but if the patients leaving get to us to decide or to help them decide I would not do the biopsy unless it's going to change what I do meaning if I'm going to sway me from surveillance to do some form of intervention like surgery or ablation therapy but when would you use a biopsy for active surveillance that's not the same question that you're answering the patient we've already decided we're going to go on active surveillance who do you biopsy who do you not so if you've decided already you're doing surveillance why would you biopsy that's the question I'm asking right so it's in my way I'm thinking of it backwards if I'm used to decide I'd use the result of the biopsy to see if I'm going to do surveillance or not so if I'm doing surveillance what is the biopsy going to tell me if I know 100% I'm doing that you know I guess my I think that's fine the thing is things don't always go the way you expect and again I think having information puts you and the patient in a position of power so there's always unexpected outcomes whether the patient gets better or the tumor does things you don't expect it to so you know even in those for me for even for cases where we know it may not change the management at that time period I still encourage a biopsy I guess so then my esteemed urology colleagues help me as a simple medical oncologist understand because we've I've had your colleagues from Philadelphia you know say that they want to avoid biopsy and they have all this data that they've published about monitoring how much growth rate there is in a small renal mass to predict whether or not the small renal mass is malignant based on a growth rate criteria so it just doesn't make it seems counterintuitive to want to biopsy that because I think the question is different is your data sets would be different if you knew there was cancer there and you were still going to observe them then I think you're using data based upon low metastatic potential and the size versus the data that exists from Uzo et al when it's a small renal mass that you don't know and you're you're basing the data set on whether it's malignant or not so I'm just confused as to I don't know the rationale I'm not aware of data from them that talks about growth rate predicting malignancy I thought that's what the small renal mass whole debate was because with the small renal mass the reason that you're observing is because there's a certain percentage of those that are going to be benign yeah and so the growth rate per year is predicting the likelihood of malignancy and that's a different and mindset that if you knew it was cancer you would want to monitor it because if it was below a certain size it wouldn't metastasize so yeah two different well not really because as it turns out oncocytomas grow and in fact they may have a higher growth rate than small renal cell carcinoma so the growth rate actually does not predict histology although I mean alterations in growth rate may trigger an intervention so for instance you know they're normally growing at a rate of two to three millimeters per year and all of a sudden it jumps up and grows seven millimeters might say holy cow we got to do something exactly um you know my practice I typically don't buy up see patients on active surveillance I you know sort of like I already decided that I'm not going to intervene so I'm not sure I really want to know and you know if the patient asks for one I'll do it but otherwise we typically don't all right I think we beat this one to death let's move on so this is a 72 year old white male who presents with uncontrolled hypertension uh he underwent abdominal imaging which revealed an asymptomatic renal mass past medical history significant for hypertension peripheral vascular disease disease with a stent and the left lower extremity physical exams unremarkable CT chest bone scan negative hemoglobin is nine creatinine is 1.3 with a GFR of 51 so GFR just means kidney function glomerular filtration rate um Dr. Chapin these are the films give us your thoughts about this and how would you how would you manage this patient so obviously there's a left renal mass um and that first image are you showing us something different or is that is that medially is that renal vein or is that nodal tissue I'm not I'm not sure doctor yeah a single image and it looks like it's potentially renal vein involvement of course do you want to show that for the patients I will I was hoping to get Dr. Chapin a consult first Dr. Crom do you see renal vein involvement looks like it this is the renal vein right here what's happening thank you somebody's got control of my mouse it looks like this is the I know how you do okay we do so this is the mass here and this is the left renal vein you could see it going all the way to the vena cava and looks like this is some sort of a tumor or filling defect here and that's pretty much it that's all so you have a locally advanced tumor with evidence of renal vein involvement what are you going to counsel the patient are you going to treat the patient what are you going to do so I would do a metastatic workup first okay we did that that was negative so in the setting of a of a renal vein involvement in the absence of metastases I would offer him a left radical nephrectomy okay so a couple questions would you do it open or would you do a laparoscopic or would you break out the robot yeah I mean anything that's been involved involvement of renal veins I've been doing them open okay I know Dr. Mateen may have a different opinion would you do a lymph node dissection or no no dissection in the absence of clinically apparent nodes only just because you and I have different opinions on this in general I would I would not necessarily do a lymph node dissection this if at the time I felt something was clinically apparent or enlarged at the during the open operation then I would do a lymph node dissection if I were to do a lymph node dissection I would include the inner order cable nodes as well so what he's saying is that at the time of surgery if he was going to do a lymph node dissection he would take out the nodes along the aorta and also between the aorta and the vena cava Dr. Mateen how would you approach this patient yeah I think open is fine if that's what you're comfortable doing I barring any other findings I think we could do a good laparoscopic procedure here I would probably remove the nodes alongside the aorta but I wouldn't really go out of my way to to do more than that okay Dr. Koran any different thoughts I would do it open just because on the left side I feel less comfortable doing the laparoscopic when there's been no vein involvement it's much easier to do it on the right side for me at least so I would do an open on the frectomy and then do at least the lymph nodes on the aorta on the left side okay would anyone consider this patient for a neoadjuvant trial if there is one available yes okay so patient undergo surgery and it's clear cell grade three obviously t3 ACE is involving the renal vein um Dr. Chapin how would you follow this patient after surgery so clear cell grade three did you take out nodes or no took out nodes nodes were negative oh yeah so I typically get a a six-week follow-up imaging and I know that that sounds aggressive to some but um CT abdomen chest abdomen and pelvis actually at six weeks to see if anything is apparent and also the set of baseline for comparison and then I'd follow them up with imaging every at least every four months initially for the first year so you follow them every four months for the first year and then beyond that every six months for two to three years depending on how things are looking and then yearly thereafter okay Dr. Mateen how would you follow this patient yeah very similarly either every three months or four months depending on some other factors um you know you talked about the stage the grade whether there's necrosis there whether there's other concerning findings what did you do with the adrenal incidentally um what would you do with the adrenal what would you do you know I think it's one of those honestly it's uh you're damned if you do and you're damned if you don't um I that's sort of my conclusion after 12 years I've removed it in cases like this and it's not involved and then they get a metastasis in the other adrenal a couple years later you don't remove it and then they maybe develop disease in that adrenal and then you wish you would have removed it and then you know three years later so I I really I don't know when it's more locally advanced like this I feel a little bit more strongly about removing it just because it's associated with a higher chance of there being micro metastatic metastatic disease in there and for all of you out there if the adrenal looks normal on CT scan um and the cancer is not directly involving it it's supposed to have about a 95 plus percent predictive value meaning it's usually not involved but it doesn't mean there can't be microscopic disease there so right and and you know particularly I found especially on the left side where the adrenal vein drains into the renal vein uh and you have a tumor thrombus it can be quite challenging to try and spare the adrenals and spirits uh it's been a strain so I took the adrenal on this side yeah good one so so can I ask uh are there guidelines whether when you should have uh when you should do like add an electomy with the nephrectomy and when you don't have to so the I mean not formal guidelines to my knowledge but I mean basically with with modern cat scanning or modern cross-sectional imaging I should say both MRI as well as cat scan if the adrenal gland is phenotypically normal on the scan then OzR you can spare it and obviously make an interruptive assessment at the time of surgery even if it's an upper pulled kidney mass even if it's an upper pulled kidney mass because a lot of times there'll be a layer of fat between the two so in this patient who has uncontrolled hypertension it could be due to the tumor it could be due to the adrenal glands of course it could be due to other reasons as well but uh in this case would you consider uh to remove the adrenal glands or at least you know look for whether there is any adrenal glands in movement with the and controlled hypertension on the on the left side yeah yeah I mean while we took it out you know I mean they did do a feal workup so the the point is that sometimes tumors of the adrenal glands such as something called a feal chromosytoma can be a source of um hormonal release that causes high blood pressure tachycardia can actually cause a stroke and he's alluding to the fact could that possibly be at play here and the answer is possibly but there are blood tests you can get to rule that out before surgery and it's important to important thing to do before surgery because you don't want the patient to have a hypertension hypertensive crisis in the middle of surgery okay let's um let's get our medical oncologist involved so this is a 49 year old gentleman who presents with gross hematuria he has no past medical or surgical history his performance status is zero his bone scan and MRI the brain are negative he has a CT chest that demonstrates bilateral pulmonary nodules he has a locally advanced tumor involving his left kidney and he also has multiple hypervascular liver nodules so here you can see this locally advanced tumor involving the involving the left kidney here very hypervascular here's the renal vein coming across to the vena cava there does not appear to be any involvement of the renal vein you can get a hint of one of these hypervascular nodules in the liver right there that whitish blush and here's another one here another whitish blush in the liver so he's got at least a couple of areas that are you know concerning within the liver and then some minimal disease in the lung you can see there's a nodule here there's a nodule here and actually uh here there's a nodule here so small volume potential lung metastases you know they're sort of still indeterminate at this point um Dr. Tenier this patient presents to you what are you going to do biopsy biopsy the renal mass and the biopsy is going is done to tell you what what cup of renal sarcosinoma he has right and why why is that important because it might guide the therapy if it is a clear cell has a different therapeutic implications different prognosis if it is non-clear cell the same way so i think a biopsy is important before we start systemic therapy because the patient does have metastatic disease to two visceral organs multiple liver multiple lung is not good to proceed with upfront cytoreductive nephrectomy so i would advise the patient against having cytoreductive nephrectomy as an upfront strategy so i would get biopsy to confirm the diagnosis of kidney cancer and to know what type it is to guide therapy okay so in most scenarios as brian alluded to the presence of liver metastases is a contraindication to performing cytoreductive nephrectomy because in our experience patients don't do well they they they have a hard time recovering and it becomes this race between you know whether or not they can recover from the surgery to get their targeted therapy versus the disease taking over their body and most of the times especially with liver mets patients will lose that race um dr hudson what are your thoughts about this patient i generally agree with that i think that um you know i would see this is a relatively a gray zone i'm sure that there are places around the country that would offer cytorectomy upfront but it's more of a judgment call um on this the things that would lead you wanting to be aggressive would be you know the age of the patient um and the fact that the disease outside of the kidney is a small amount of the total cancer burden that the patient has so if you did the surgery and he recovered you would have effectively removed 70 percent or greater of the tumor volume in the patient um so so i think knowing the symptoms the patients having coming in the door would be useful um knowing if you could um how rapidly things were progressing um would help you in in situations where you had rapidly progressing disease where you knew patients had different imaging over the past couple months that you knew the cancer was progressing quickly that would be clear indication not to proceed with side reductive surgery so um i i i hear and understand the the concerns about the liver metastases it's it's a very this is a real life case um real life patient you know and it's a tough decision to make um i can just share and i'm sure you know that around the country you'd be getting different responses okay but we want your response well that's what i'm saying i think in this particular situation um with all things being said if you told me the patient had um was completely asymptomatic um and was and wanted to be aggressive i would lean towards side reductive surgery if the patient was having any degree of hypercalcemia or any type of poor risk factor on the traditional hang criteria um i would lean against that and would proceed forward with targeted therapy and what would that target therapy be um either a votrian or suitent dr teneer you never mentioned what therapy you'd give ideally participation in clinical trial but i think either one of these two uh are acceptable okay um dr uh karam what are your thoughts so i want to ask dr teneer would this patient be or would you not send him for consideration for surgery until you have biopsy proven liver meds or are we going to consider those tiny areas liver meds without a biopsy i know they're very small and it's hard to biopsy them but maybe they're hemangiomas maybe they're nothing so this patient might be losing an opportunity again just for the sake of discussion i think if you have a uh uh good city or an mri and these clearly uh you can tell that these are not hemangiomas but rather uh liver metastasis i don't think really necessarily there's really a need to do a liver biopsy now if you are uh not sure about liver uh metastasis or not then i think you could do a biopsy of one of those liver lesions instead of biopsy the kidney biopsy deliver and uh if then it is definitely metastatic then you have the answer but i agree i think we need to get more data about uh the other parameters that we take into consideration to uh categorize the risk of this patient in terms of this good risk intermediate risk or favorable what would those be risk you know anemia hypercalcemia as Tom mentioned serum ldh platelets white blood cell count i understand his performance as zero but i think these other laboratory they're all normal okay so he has an intermediate risk disease by virtue of presenting with advanced disease uh and uh so that's one risk factor and then he has uh didn't you say anemia wasn't here or the hemoglobin is okay hemoglobin is okay how bad is his gross inventory i mean i think that's also an important factor to consider if the the bulk of the tumor in this patient is in that kidney and looks like from the scans more than 95 percent of the tumor in this patient's body is in the kidney and the patient's having severe yeah one of the sort of grossing material is urine's clear now okay i mean that's just a factor that we should consider even though the patient might have small liver metastasis it's hard for me to buy not wanting to do surgery that can affect me for small volume liver disease and i can i see the point that if you have more substantial liver disease um but those are very tiny and it's just again i don't have your experience and i know we're all we're all kind of creatures of where we trained in our experience so um if you have experience in house of you you tend to pattern your your treatment course for that but understand as patients that this is a gray area um that the when to do cytoreductive nephrectomy we don't want to offer that that type of procedure to patients who who um aren't going to do well with opera recovery from the operation so it's very very tough sometimes all right so let's just have a show of hands who would do cytoreductive nephrectomy upfront cytoreductive nephrectomy and who would not it's good so we're all in agreement excellent no i i i want to comment this patient is only 49 you know he has lots of tumors in the body uh he has good performance status you know if you theoretically if you remove a large burden of tumor in the from the patient's body he might do well i know you know the data show that patients with liver metastasis will not do very well but you know considering his age considering his doing really well considering this physiology you know i would i would give it a try if my surgeon colleagues agree with me so i think it's not the the fact that you're not going to offer the patient surgery at all it's whether you do it upfront or you do it after a certain number of cycles of systemic therapy to assure yourself that the disease is not rapidly progressing and then you could do a delayed nephrectomy i mean that's the whole argument about the uh uh third time trial is the timing of the nephrectomy is it upfront or is it delayed and i think this somebody with liver mats whether large or small i mean if there are multiple uh i would uh be concerned about the possibility of this patient having uh rapidly progressive disease uh you know post up you know six weeks later to allow healing unless the patient is having you know uh you know refractory uh continuous gross immature pain and then you do it in a palliative manner and advising the patient that there is a chance that the patient will have progressive disease postoperatively and then uh you know if you uh you know want to give the patient high dose r2 you believe in high dose r2 you work at a center where or the patient has access to a center that is experienced in giving high dose r2 and you think this is what you're going to treat the patient with upfront then that's an argument for doing upfront cytokinectorectomy is to send the patient for high dose r2 you know the it's a great case because i think i definitely get very concerned when i see liver metastasis but i think tom makes a really good point um you know the other thing we know is that when you can we can remove the overwhelming bulk of disease those patients do better that's based on sort of very limited and biased data but still that's what we have what i do want to bring up and i hope i'm not taking your fire chris but it's the the cope with the criteria that actually you developed with steve cope and what what chris did here was they identified six factors that and if you had basically more than three of them correct if you had more than three of them then you as a patient you would not really benefit from surgery and as best as i can tell this patient has one or two of those one the liver and just liver anemia anemia wasn't in the list right yeah so and those uh those factors were lymph nodes in the abdomen lymph nodes in the chest uh several blood markers that were high um what else was it ldh and alfos and liver disease and and the presence of symptoms from metastasis yeah so in that sense in terms of looking for other pieces of evidence to guide you you know i normally would not recommend cytoreductive surgery for someone with liver mets but they are very small and it's a young patient who's going to recover pretty speedily from a big operation and so i actually in this case would offer that was my rationale for offering surgery first so from my perspective liver mets do make me nervous and regardless of the small volume of disease it can rapidly become a high volume disease very quickly and i think it's interesting that you know dr teneer waxed philosophically about why he would not send this patient for cytoreductive nephrectomy it's actually his patient and he sent him to me for cytoreductive nephrectomy um but the goal was to enroll him in the ADAPT trial which you've heard about earlier today uh the ADAPT trial is uh a trial where patients are randomized to receive a personalized dendritic cell vaccine basically their tremors process to make a vaccine uh plus in it versus in it and below and so we both felt that this young gentleman with low volume disease vast majority could be removed with nephrectomy that we would sort of break our position on on cytoreductive nephrectomy in the presence of liver metastases and and offer him this so we took him to surgery we did the left side of reductive nephrectomy and also biopsy one of the nodules in the liver it did turn out to be positive for metastatic disease uh his um final stage was t3a n0 m1 firman's grade 3 so it just means locally advanced tumor with metastatic disease clear cell histology and he comes back now in follow-up and you can see that those tiny little white blushes have become innumerable so he's got extensive disease present all these little white spots are all metastases in his liver so he has progressed significantly which we expect after cytoreductive surgery he's also incidentally got a little tiny renal mass right here which we didn't do anything about at the time of surgery and just uh would recommend continue to follow uh and his lung disease really hasn't uh changed dramatically um there's you know the same small spots there's same number of small spots but hasn't changed significantly there is some enlargement of hyaluronodes so basically some lymph nodes in the mediastinum have increased in size that were not increased in size prior to surgery so um Dr. Taneer this patient comes back to you at six weeks with these findings what are your recommendations for him so he rolled him on the trial so uh he's so you wouldn't change that recommendation you would keep him on I mean depends did he develop also now hypercalcemia high serum elevation of his high serum at the age so I think we already enrolled him in the trial that was the motivation to break the rule and do the upfront diffraction because we have a exciting trial with the vaccine and to do to be eligible for the trial you had to not start systemic therapy but harvest the kidney to harvest the uh to to produce the vaccine to allow the patient to get uh sunetin a plus vaccine so that was the reason we broke the rule here so I think if unless the performance status declines this precipitously unless he's developing now porous features with high serum ldh high serum calcium uh high platelets high white blood cell count if if he did not develop these uh uh poor prognosis uh uh factors then I think uh proceeding with sunetin a plus the the our any vaccine all right time you don't have this trial at your center what would you offer that trials great trial um we just didn't choose just because of logistical reasons with with the urology department but but that trial is great because you're not denying patients act um an act of drug which is currently the standard um so suninib um there's nothing proven better than that agent at shrinking the tumor and so on on the trial you mentioned they get that regardless the vaccine's just a plus so in standard practice outside of a clinical trial setting um they would um most likely either get suninib or votrant um that's a standard okay Brian you look like you want to say something I'm just going to comment just to make sure that people are aware of the you know at a 49 year old with the outcome of surgery is no complication and things went well and in six weeks he's going on therapy you know you probably didn't lose too much but in the setting of where if this were an older patient maybe poor nutritional status even if they didn't meet the risk factors I mean this could be detrimental if this patient had a one complication or a fascial dehiscence or was delayed therapy by months before while those liver meds progressed so um you know we obviously are taking all that to account when we're thinking about these things but I mean I think it's really important that we impress upon the importance of um of looking at kind of the the risk for the of the surgery itself and whether or not these patients are going to be delayed therapy that's active yeah from my perspective in the absence of a clinical trial that this patient was going to be directed towards I probably would not have offered him cytoreductive surgery I would have offered him systemic therapy up front with possible delayed cytoreductive surgery if they had a good response that would have been my approach in this patient yeah I don't know that one's right over the other but I would have agreed with you I would have done the same thing but um I work with nothing right I wouldn't have all right let's do one more case and then we'll break that which I've gone get the lunches and bring them back in here and we'll continue on with the case presentations while we eat lunch uh so this is uh this is an interesting case this is a 72 year old African American gentleman initially presented to an outside physician back in 2003 with an incidental finding of a left renal mass and he underwent left partial refractomy margins were negative it was a type 2 papillary T1a tumor so stage one type 2 papillary tumor a node dissection was not done at the time of surgery he did well until 2007 and then he developed a left renal recurrence and he underwent a salvage left radical nephrectomy at the time the left adrenal gland was left in situ because it was radiographically and phenotypically normal at the time of surgery and the final pathology demonstrated a type 2 papillary right renal cell carcinoma stage T1b with negative margins he did well until 2009 and then he developed an enlarging mass in the right adrenal gland and he underwent a right adrenalectomy thank god we spared that left adrenal and this revealed metastatic type 2 papillary renal cell carcinoma he did well until 2010 and then he developed a right adrenal mass sorry right adrenal fossa recurrence as well as a left adrenal mass and he comes to MD Anderson his past medical history is fairly extensive he has a history of hypertension and ulcerative colitis he's had innumerable surgeries he's had a total abdominal coletomy for his ulcerative colitis he's had a left partial nephrectomy a left radical nephrectomy a right adrenal ectomy he's had lung surgery in the past for a benign tumor and he's had a chirp or a perception of the prostate you could see the medicines he's on he does have a smoking history but quit back in 2003 and he has fairly significant renal insufficiency following his nephrectomy because of the hypertension and so his his scans could not be done with contrast they had to be done without contrast but just to show you so here's the vena cava here's the aorta he's got this mass present where the right adrenal gland used to be which is a recurrence in the right adrenal fossa and he also has this locally advanced mass here where the left adrenal gland should be you can see this is the pancreas draped over it here's the beginning of the spleen but the pancreas is sort of intimately involved with it very large mass and here you can see the extent of the mass extending down along the aorta so again he has an adrenal fossa recurrence after adrenal ectomy and he has what looks to be a locally advanced left adrenal metastasis with extension down along the lateral aspect of the vena cava and has probably a significant chance of having a hostile abdomen from all of the surgery that he's had done in the past and he comes down to the Anderson and sits down with dr. Chapin and dr. Chapin what are your recommendations for this patient it's obviously a difficult problem i mean the um in patients who've had retroprenia recurrences who undergo re-resection i mean there is a real mortality risk dying of the operation itself or dying while in the hospital um this patient's had multiple abdominal surgeries would it be a difficult at best even to get access you're also dealing with other organs that are assumed to be involved with the tumor at this time although in the absence of other metastatic disease a lot of this appears to be local tumor so i honestly it'd be a difficult problem and i probably would see consultation from you you're killing me and i would i'm i'm i'm not i'm not in the hospital i'm i'm traveling so um you're on your own what are you gonna do um you know i i there's not really good systemic therapy for this and in the absence of distant disease i mean i think if the patient wants to to go for it you tend to be heroic here and try to go for it but uh so i'd be very hesitant this is progressing while you're talking why don't you tell us what you're gonna do i probably would seek the help of some of my surgeon colleagues for hepatobiliary just to make sure i don't need assistance with the pancreas and uh i would do a midline approach to resect his left fossa recurrence and his right adrenal recurrence adrenal fossa recurrence okay and he would not have any adrenal glands left so what what are the implications of that he'd have to be on on replacement therapy which is uh mineral corticoid and the glupin corticoid so prednisone in florida for the rest of his life for yeah what's left of dr crumb dr chappan's office next to yours uh he comes by for consultation what would you tell him just a quick question is this something significant here or just a little artifact i don't know guys i have two pictures to look at so since you've seen the films just to see if it's a local recurrence but i just want to close it is so if the first thing to do is to make sure that to do a complete metastatic work up so which we've done and it's negative to summarize it if the patient is healthy enough and willing to take the risk of doing an operation um in the absence of metastatic disease and in the absence of effective drugs his only chance of prolonging his life is to go back to surgery and removing the left adrenal gland and the recurrence on the right side completely to find healthy enough because because he's got renal insufficiency to the point that he can't get contrast for ct and he's got a history of hypertension and had multiple abdominal surgeries but that's that healthy to you yes and in our clinics i mean this is standard so if the patient what we normally do is send our patients to the internal medicine clinic for evaluation before major surgery and if the patient can tolerate an operation and it's his only chance of survival then that's what we have to do okay there's another another look for you to see so i didn't know that one thing to point out about his disease kinetics is you know his disease was fairly indolent over the course of about the first seven years and then suddenly in the past this recurred within a year right last surgery was 2009 yeah this was 2010 so i think that's a that's something to make note of because it's for whatever reason the tumor had a genetic shift or something and now it's not quite as you know it's sort of sputtering along over the course of six seven years and and now with the course of one year it did more than it did the previous you know six okay so what would you do oh i'd actually would call nizar because i i would be in you know he's got a lot of experience with unconventional histologies or non-clear cell and see if there's either a clinical trial or there's something off trial that may be worth trying but uh that does not negate anything that dr carum said his real chance is surgery but the fact is the likelihood is is that he would recur pretty quickly afterward um but i would still you know explore all possibilities with nizar so as it turns out he has fairly significant renal insufficiency with the gfr of 27 he is an emigrate because alfos is minimally elevated but his bone scan is negative and the patient says all right you know what i'm really tired of having surgery so uh dr tenir uh he comes over to your clinic what are you gonna tell him unfortunately he is not a candidate for a clinical trial because of his renal insufficiency so as we discussed this morning uh all these good therapies that we have uh unfortunately there is really they're not established or they're not they have not been demonstrated to be effective in the non-clear cell histology especially papillary type two papillary type two uh in my opinion my experience uh is one of the toughest ones to to treat uh there have been retrospective studies we did a single arm uh phase two trial in non-clear cell and we had 27 patients with papillary RCC uh we treated with sunitinib on phase two trial and the results uh were not uh impressive at all in fact of the 27 patients with papillary treated with sunitinib um zero responded and the median progression free survival was 1.6 months we published this in 2012 in european neurology now some of these patients may maybe may maybe were like uh him with comorbid illnesses some may have had performance stats of two uh but these drugs that we discussed this morning don't really produce the results that uh we see with clear cell so i would uh try to convince the patient and convince the surgeon to go and do surgery now if he's adamant against have surgery uh he's adamant then then we will try uh try sunitinib uh you know for sunitinib would be your first choice well i will try to see if his insurance would cover uh off-label drugs is independently wealthy you can cover it by whatever so why don't you tell us what you would choose well i think the the the drug that tom mentioned this morning uh cometric or uh cabuzantinib would be uh a drug that i would consider uh you know tarsiva urlotinib has been shown to have some activity in what he wants to know what dr teneer would recommend i would recommend if his insurance would cover uh cabuzantinib then we'll get him cabuzantinib okay and if he's indigent what would you recommend then uh you know again if he's not going to be able to get urlotinib or cabuzantinib then uh uh what did you tell us about his performance status as well and performance status is one yeah i mean then you can try sunitinib and and and tell him that the results are not uh that good but we can try that okay there's one other option what's that that is to either use his archival tissue or do a biopsy and have it go through the uh in our group it would be the phase one group or the molecular markers group and um you know basically what happens now is that it's so much easier to test for the gene mutations in these tumors and now what in fact we just got an email this week where they've been able to go from instead of testing 50 they can test 400 known mutations and some of those mutations are targetable meaning that there's drugs that will act against that so that would be another option and actually i think he would fit that um that trial jj had you you and i have done a couple of cases like this what's that i totally agree with you however phase one we're declining him up front because his kidney function is low so but uh even in that case you can still uh do the xm sequencing uh his primary type two so it's uh possible that he has cmed mutation and if that's the case just like what doctor to near said we can try uh covers that in it which is a cmed inhibitor so if you can match the mutation with the drug and the likelihood likelihood for success can be up to you know 70 percent um so okay so your so your choice would be covers that in it if you can get it otherwise um otherwise i mean you can try one of the tki's you know yeah what one do you want to try i would uh agree with doctor to near try uh son internet okay tom any different thoughts no all the above i tend to um use nexivar um a lot for my non-traditional histologies that don't fit any other pigeonhole for anything and um with anecdotal evidence of some people do well for long periods of time and one strategy in the sky who's not going to do well he has a lot of negative features up front with his disease his past medical history his borderline renal insufficiency i mean he's in 2 point gfr of 27 for you all in the room the normal should be in the 60 to 70 range um for someone so he has impaired kidney function he probably my concerns going to surgery right away is that he wouldn't make it through the surgery he'd come up with a complication so one of the things that could stratifies if you put him on an agent and he was had a period of stable disease um that you could contemplate um some type of resection later because at least you know that his his he wasn't exploding because it seems like my experience has been whenever we've taken patients for multiple metastectomies that um one of the biggest concerns is it just pops right up again and it's spreading while you're recovering um and so if you could if you if he was able to demonstrate control on a targeted therapy although that may be rare not common maybe one in five um but if he declared himself that way um then you he may have a chance um with being more aggressive surgically okay thankfully his disease hasn't progressed while you guys have been battling on up here um he was initially treated with synitinib stable disease progression in five months changed to everlimus stable disease significant toxicity noted with both the synitinib as well as the emberlimus um what do you think cut cut cut cut cut cut him he may not think surgery is so bad now after getting all that poison anybody disagree with taking him to surgery okay he was taken to the operating room had an exploratory lap left a radical adrenalectomy excision of the right retroperitoneal mass uh it was actually invading into the gallbladder so you're on block polycystectomy and also partial hepatectomy um this was done in April of 2011 you can see the pathology thankfully had a good surgeon so he recovered nicely from surgery and did well until October of 2013 he then uh showed up on staging evaluation to have a para aortic renal recurrence with CT chest and bone scan that were negative his cratin is kidney functions even worse with a GFR of 23 crating of 3.19 although he's no therapy after surgery or no would you have given him therapy after surgery well I wouldn't have done it that would be somewhat malpractice but I would be curious because most of the time the medical oncologist would like to give more he uh so well okay let's ask him Dr. Tenir would you have given this guy's uh Tom said no no as I said I was arguing for surgery all the way but no I think after the surgery you rendered him without evidence of disease you resected everything visible in the abdomen so I would have followed him like you did so would anybody have given him systemic therapy after the surgery no okay good all right so um here's his uh here's his films and you can see I'll show the audience here he's got this one little area of recurrence right here right next to the aorta uh his kidney functions even worse and he has an even more hostile abdomen because of his previous multiple multiple surgeries so again brief please Dr let's see Dr. Mateen what would you do well he had a reasonable response to the first couple of agents um and so I would uh again call Tom or uh these are and talk to them about putting him back on therapy an alternative would be to observe him for a short period of time just to see if he's developing explosive disease just to spare him you know um the suffering but the suffering of what treatment are you doing surgery no no I wouldn't offer surgery you would not offer surgery okay Dr. Karam so now it's been two and a half years since his last operation it's been three years actually three years so I mean I agree with what Dr. Mateen said the other thing is I would consult with my interventional radiology colleagues to see if there is any way they can do an ablation on this mass I know it's very close to the aorta but at least it's a question worth asking during the course of the disease while it's still small or if it can even be shrunken you do realize this is small ball right here sitting on top of it well can't see it it's pretty dark and I have one picture to look at but if you say so I'll take your word for it it is trust me uh but that's the only other thing I would not go back to do surgery at this point okay Dr. Chapin yeah I mean the same same as what the other two said I mean essentially systemic but sending back to Dr. Tenier for consideration of systemic treatments and then see where things go over the next course of the next year so for this solitary small recurrence in the retroperitoneum all the surgeons say no medical and college anybody in medical and college do you want to do surgery I think the same is surgery for today so I'm sorry I said it again the theme is surgery today so you would offer surgery well at least some local intervention if it's possible you know I don't I don't know if if you repeat like those target agents whether they you know the tumor apparently didn't respond it became refractory if you treat I don't know the you know how much chance you have for this to respond yeah so to be honest with you from my perspective he did not tolerate the targeted therapy as well he had a lot of toxicity his renal function is terrible this is a small isolated recurrence we took him to surgery and he had a salvage resection there's the pathology margins are all negative he also took out some of the lymph nodes and you know it's been three months so far so good he was able to get through the surgery fairly well but I thought my feeling at the time was that you know additional systemic therapy we know what this thing is it's not going to shrink it's not going to make it go away it's going to make him feel terrible and probably make him a worse surgical candidate so you know I thought that the aggressive local resection was probably the best way to go all right so why don't we take just literally five minutes to run out and get some lunch and then bring it back in here and then we'll continue the grilling and then you know so You're welcome to bring your lunch if you want, we know you eat, we've had a good time. You're welcome to bring your lunch if you want, we know you eat. We've had a few casualties. So one of the things we're remiss about, it's my fault and I apologize, but did anyone have any questions that they wanted to ask? I was asked one question during the break that I just wanted to allude to and that is, you know, one of the concerns when you integrate systemic therapy with surgery is the issues of wound healing, which I brought up during my talk. And, you know, it's very important to understand that when you commit to performing a surgical procedure on a patient, they are going to need somewhere between four and six weeks of time to recover from that surgery before they can get any targeted therapy, regardless of what's going on. And that's always, at times, not always, but at times it can be a real crapshoot where, you know, you'll have a patient that you operate on whose disease for whatever reasons decides to explode after surgery and you sit there and you watch this disease consume this person and there's really almost nothing you can do because of the dangers associated with receiving targeted therapy and the issues associated with wound healing. Did anyone else have any other questions? If you do, we'd ask you to come to the microphone just so that we can record the question. Do you have a question? Anyone? If not, we'll proceed with some more cases. And, you know, if questions do come up, please don't hesitate to get up and come to the microphone and we'd be happy to take those questions at any time. If you have a question about the case, or if you have a question about one of these guys' judgment, just step up to the mic and let us know. All right, with that said, why don't we go ahead and move on? So the next case is a 50-year-old gentleman who presents with shortness of breath and chest pain. Those are sort of classic symptoms for somebody who has a pulmonary embolism that's always a concern. He reports a 60-pound weight loss and fatigue over the last six months. He had a CT which was negative for metastatic disease, but also negative for pulmonary embolism, importantly. He has some evidence of renal insufficiency with a creatinine of 1.49 GFR of 50. He's got some anemia, although his LDH and LFTs are all within normal limits. LFT stands for liver function test. LDH is lactate dehydrogenase, which is just a blood test that we get an enzyme that circulates in the blood. And here are his films. So what we can see is he appears to have a tumor originating in the right kidney. And this is a tumor thrombus that extends up the vena cava all the way into the heart. Here's the heart right here. And you can see that he's got a very large tumor thrombus present within the right atrium, which is one of the chambers of the heart. Here's another view, which again shows a locally advanced tumor involving the right kidney here with a thrombus going up to the heart. And here's a cross-sectional image. Here's the renal artery going to the kidney. Here's the tumor invading into the vena cava right here and a locally advanced tumor involving the right kidney. The left kidney appears to be normal and his metastatic evaluation appears to be negative. So with that said, Dr. Karam, you're always whining that you don't have enough patients at clinics. So this guy shows up in clinic for you. What are you going to do? Write an ephrectomy and IVC thrombectomy and atrial thrombectomy in conjunction with our vascular surgery colleagues. Okay. What would your approach be? What incision would you make? I would do a midline incision and then the vascular surgeon might decide to do a sternotomy if they cannot get the heart thrombus from the abdomen. So that will be one long incision basically from the neck down all the way to the pubic bone. Okay. But it could be done in different ways, but that's the approach I would do. Okay. Dr. Chapin, presumably you're allowed to do this. What would be your approach? Yeah. So in conjunction with you or Dr. Karam or Dr. Matin, I would perform a right radical and an ephrectomy and thrombectomy with the help of the vascular team. Again, I do the same through a midline approach. In the absence of, you know, we talk about lymph node dissections and you're probably either going to bring that up or if you haven't already, I would do a lymph node dissection and this just as a function of trying to dissect out the vessels anyway. Would anybody consider preoperative embolization? So just for the audience, preoperative embolization means that just prior to surgery, basically putting a cork in the renal artery to cut up blood flow to the kidney with the tumor in it. And in past series, that is actually that used to be the sort of standard approach for this type of this type of a tumor. Would anyone consider it? No. Okay. In the old days we used to do that and the thought process behind it was that these tumor thrombi are very vascular. And so by cutting up blood flow to the tumor thrombus, the hope was that you could get it to shrink down and avoid the complications associated with having a median sternotomy and having to be put on cardiopulmonary bypass and so forth. And there are anecdotes in the literature where you'll see this tumor thrombus much like this that shrinks way, way down almost to the renal vein. The problem is that that almost never happens. And so the morbidity or the side effects associated with embolization are probably not worth the potential benefits. And so we rarely, if ever, will embolize patients nowadays before surgery. Can I ask you if the patient had compromised liver function, would you do it in that scenario? Not in the setting of planning to do the operation, but in the setting of trying to treat what's there? That's a good question. I'll throw that one over to Dr. Karam. What do you think? So I had this in my presentation, but just for the sake of time I didn't include it. So what you're referring to is when the tumor thrombus and the vena cava goes to the veins of the liver and basically blocks the liver outflow. And that's called Bud Kiari syndrome. And for those patients, we routinely do not take them to surgery immediately, but we first do the embolization procedure to try to shrink the tumor from those veins and allow the liver to recover. And then if they recover well, we will take them to do the operation. Yeah, so in our experience with Bud Kiari syndrome, and Bud Kiari, Bud was a doctor, and Kiari was a doctor who described the syndrome. It's a hepatic outflow obstruction associated with abnormalities in LFTs. They develop abdominal ascites. They develop lower extremity edema. And they develop liver profusion abnormalities, clotting factors that the liver produced become abnormal. And in our experience with taking these patients to surgery, the in-hospital mortality rate is in excess of 80%, meaning that 80% of the time these patients that never leave the hospital, they die in the hospital. So now we approach them with this embolization process, again, hoping that the tumor thrombus is vascular, hoping that it shrinks a little bit so that they can again regain hepatic outflow and return their liver function to normal. The problem with embolization, however, is that if you do not operate within the first 48 hours after embolization, you have to wait three months. And the reason for that is that the changes that occur as a consequence of embolization and the abdomen, it's like a bomb went off in there. And the tissue planes are basically like wet Kleenex. So trying to take somebody to the operating room before the embolization has had time to mature can be a catastrophe. How successful is this embolization? It's hard to say because, you know, the only ones we know about are the success stories. The ones that are not successful usually go home and die and we don't hear about them. So this patient underwent right radical nephrectomy, IBC thrombectomy. You can see the pathology here. He had evidence of rabdoid features. That sounds bad. 20 to 30 percent. And it was a T3C tumor obviously because it was up to the renal, up to the right atrium. No evidence of any adenopathy. Dr. Karam, rabdoid. Sounds weird. Yes, that's an aggressive suck type of kidney cancer. And you hear in this situation is clear cell kidney cancer. You could see it alone or you could see it with another very aggressive tumor called sarcomatoid. These are all very high grade tumors, you know, grade three or four. And they basically all it's saying here we have a patient who has an advanced tumor going all the way to the heart and high grade tumor. So this patient is at a very high risk of recurrence in the future, which, you know, goes down to your question there. How often would you, you know, follow the patient, how would you treat him? Unless there's an adjuvant clinical trial, the standard would be to just watch the patient with imaging, which we would do every three months or so the first year. If he wants to know his risk of recurrence, what number are you going to tell him? I'd say at least 50 percent. 50 percent risk of recurrence? At least. Dr. Matin, you agree with that? Yes, perfectly. Anybody else have any differing opinion? Sarcomatoid is really different from sarcomatoid. And all it says, this is a high grade tumor. It is, like, chose the tumor cells around, but it is different than sarcomatoid. All it says is basically high grade. Okay. So here's a 53-year-old white female who presents with low back pain and weight loss. She has a past medical history significant preservical cancer, which was treated with a cone biopsy. And she had a CT chest and an MRI of the brain that was negative. All of her laboratory studies are within normal limits. And here's her films. So there's a couple of points here. You can see she's got a tumor involving her right kidney. You can see that here in the cross-section. But she's also got evidence of sacral involvement. You can see she's got a lesion right there. And we'll see that on the next film. Again, you can see she's got tumor involving her sacrum. So it's a metastasis from the kidney tumor. Well, presumably a metastasis from the kidney tumor to the sacrum. You can see it again here. Everyone appreciate that? Okay. So first I'll throw it out to Dr. Gao. This patient shows up in your clinic. What are you going to tell him? First of all, you want to make sure the diagnosis. So she has a history of cervical cancer. I assume that's an early stage, but still with two sides of disease. So you want to... I would biopsy of that sacrum mass. So you would biopsy of the sacral mass? Yeah. Or mass, okay. Dr. Krom, do you agree with that approach? Yes. So you would biopsy of the sacrum mass? Yes. Dr. Tenier, this is actually your patient. What did you do? Yes, I would biopsy. Either the mass in the kidney or the sacrum mass. Okay. Here's the bone scan. And again, that just demonstrates just for you all. The hotspot right here corresponds to the area of uptake or the area of concern on the CT scan, indicating that it might represent a metastasis. So everyone has said that they would do a biopsy. Anybody differ from that? I would just... We definitely want to biopsy of the sacrum mass over the kidney primarily. That would be my choice. Yeah, the problem... Nobody actually did... You didn't do a biopsy. No. She was... It was presumed that this represented metastasis. And I guess I'm... You know, cervical cancer metastasizing to bone and as well as to the kidney. I think that's... I'm not even like... I'm less concerned about the cervix since it was treated with the comb biopsy, but something else. Like? Like another primary. Like? Primary bone sarcoma or osteo... Bone sarcoma metastasizing to the kidney? No, I think that could be two separate primaries. Okay. But I'd want to know what the sacral lesion was before I went ahead with treating the kidney. Why? Because if it turned out that it was metastatic kidney, then there is possibly options for clinical trial in like a pre-surgical type setting. Sarcoma and the patient needs kidney function for chemotherapy for sarcoma, then I would treat the sarcoma with chemo first and then do that effect to me at a later time. But the chance of this being another primary, it's always yes in the partial diagnosis, but that's practically, practically speaking, this is very unlikely to be anything else but renal cell would match to the sacrum. I mean, this is a pattern of behavior of RCC. It's unlikely. We've seen, I mean, we've seen we have patients together the patient has multiple lymph node enlargement up and down, you know, from the chest all the way to the pelvis and has renal mass. Yes, there you would see one of those lymph nodes because the patient could have very well a lymphoma and a renal concurrently. I see all the time two malignancies concurrent. Both sometimes can be metastatic, but this is not, it's unlikely to be something else other than kidney going to the sacrum. We have a saying in medicine or in med school you learn said, the saying goes, when you hear hoof beats, think horses, not zebras. Apparently Dr. Karam and Dr. Chapin didn't go to that medical school. But we work here at MD Anderson. So the patient subsequently was referred to me and I don't want to set a reductive nefrectomy. She received radiation therapy to her pelvis for the pelvis metastasis and her tumor was sent for processing and she too is being enrolled in the ADAPT trial which is again the dendritic cell vaccine plus synidine versus synidine below. Jose and I have a question to ask you. Would you have considered doing a partial nefrectomy in that patient? That was what I was going to ask you actually. Yes, I would have, that's why I'm asking. Going back. So Dr. Karam, I believe you have published or just now publishing the role of partial nefrectomy in metastatic disease. What is the role of partial nefrectomy in the setting of metastatic disease? The application that we just have is a small number of patients over a long duration. It's about 33 patients but the bottom line is whenever it's technically feasible to do a partial nefrectomy that's not a heroic type of partial nefrectomy and this is a feasible partial nefrectomy we should consider it especially if the patient has borderline kidney function. Okay, so this patient doesn't have borderline kidney functions. She has normal contralateral kidney. So, you know, I agree with you you could do a partial nefrectomy here. So there's two, I have two challenges, two things that occur to me for that because I did consider it. So first of all, it would probably be would you do it robotically or would you do it open? This looks like it's do robotically based on this picture. I mean it looks like it's not invading into anything like a collecting system but... You would not do this robotically. No, you would not. Having said that, when we talk to the patient with a metastatic disease about a partial nefrectomy we have to be very careful and tell them that there is a higher risk of complications with partial nefrectomies. So that might delay their receiving targeted therapy. So if we are doing a partial I think we have to be sure that we can do a good partial with the lowest possible complication rate so that we don't mess their chances in getting a clinical trial. So if it's a large mass invading into other things I would definitely do a partial but for things that are doable I think we should at least entertain the idea. My approach would largely rest on whether or not I was planning on doing a lymph node dissection at the time and in the setting of metastatic disease I think there's a lot of thoughts about whether or not you do a lymph node dissection I think in this patient my thought is in this patient with a solitary metastasis doing a lymph node dissection would be negative. If your plan is to treat that metastasis possible with a resection later on by metastasectomy. Do you think that metastasis is resectable? No I don't think it is at this point but you could treat it locally. My point is in the absence of other metastatic sites I think a lymph node dissection may provide some information here. And then the patient develops callous societies and has a drain. Sure there's risks with everything. She had a radical would have absolutely done a partial would have done a robotic. The challenge with that though is again going back to the statement that I made before we started the case presentations again if she has a complication urine leak bleed what have you that could potentially prevent her from getting systemic therapy for some period of time because you're going to need to have the urine leak heal up beforehand. So if she had a complication related to the partial I think we're overstating those complications you know I mean urine leaks are very unusual in our practice these days. Not with a tumor that size. And you know the overwhelming majority of the kidney is uninvolved by tumor. You have 90% of the kidney which is completely healthy. You know the real risk would be hemorrhage but hemorrhage is something we can manage fairly quickly and I don't think it would delay her therapy overtly. So that would be my approach. I would agree that if it's that's pretty clear cut that that's separate. I think that that would be on the lower end of the complication rate compared to something that was maybe a very endophytic or tumor that's inside the capsule of the kidney and not really extending outside of the kidney. So I think that's a scenario where it might be an option. I agree I'm not a surgeon but I agree a portion of rectomy would have been the preferred approach for treating the primary and I would not do lymph known dissection in the space with metastatic disease to bone absence of obvious enlarged lymph nodes by CT or at the time of surgery. So that's added time and it's really not going to help her to have RPLND in her case. And so the thought again the thought process from my perspective was we could do a minimally invasive procedure that she's much likely to recover from very rapidly and go on to receive systemic therapy if she needed it if she didn't need it she could just be observed. So let's move on. She presents with cough, lower extremia edema. No real urologic complaints. Lab work indicates hypercalcemia and anemia imaging is obtained. She has a performance status of 1. She has a past history of myasthenia gravus gastroesophageal reflex disease and also ADHD. She's had a C-section and had a thymectomy C-section times 3 in my thymectomy in the past for her myasthenia gravus. And here's a locally advanced tumor involving the right kidney with an IBC thrombus. And again, not to belabor this. Dr. Karam, how would you approach this? Does she have any metastatic disease? CT chest was negative, bone scan was negative. So the patient has poor risk disease with the kidney being there and then having at least two lab functions abnormal. This is no metastatic disease. What do you mean she has poor risk disease? Yeah. I mean just the poor risk features with the other lab studies but I think surgery would be her best option here. But then a frectomy and thrombectomy. Okay, would you do another section? Yeah, I mean for thrombectomies it would be part of the procedure to free up the vessel. So we would do an lymph node dissection as part of the operation for all the IBC or most of the IBC thrombi. Is her lower extremity edema because of compression or IBC syndrome? Or does she have also hypoalbuminemia? Do we know her serum albumin? Serum albumin is normal. So yeah, the lower extremity edema is just related to back pressure from the IBC. So she underwent a radical nephrectomy and she had greater than 95% sarcomatoid slash rabdoid de-differentiation. The tumor was invading into the renal vein and also into the arterial wall and was present at the margin of her section. So Dr. Chapin, how would you follow this patient? What would you recommend for her? Yeah, this is unfortunate because of the sarcomatoid findings, but also the fact that you have a positive margin. There's a very high likelihood of recurrence, whether it be at that margin or whether it be in the FOSSA or whether it be dis-in-disease. So I would do what I do for most high-risk patients. If there wasn't a trial available I would follow them closely with the six-week follow-up imaging followed by probably every three-month imaging as well. Okay. Dr. Crom, you agree? Yeah, about the follow-up I would do the same just follow-up at six weeks because these patients have a very high chance of recurring early, but unfortunately this patient probably doesn't qualify for clinical trials even if we had them because of the arterial margin, which we don't see arterial margins uncommonly at all in kidney cancer, but with sarcomatoid that's not surprising at all. So I would just follow her, like Brian said, six weeks initially in every three months. Dr. Matin, anything? No different. Medical oncologist, any role for systemic therapy here in this setting? Not of protocol. And if he is not a candidate for improv because of the positive surgical margin then we will follow her as mentioned, three months post up with scans and then I think with this histology I would probably get at least three scans per year maybe even four scans per year every three months. Dr. Crom, what would you assess this lady's risk of having her tumor come back? Unfortunately I think it's more than 90% chance of it coming back. And where would it come back if it comes back? With the sarcomatoid it will probably come back at the renal fossa, the lymph nodes, the liver and the lung among other places. This is a very aggressive tumor and unfortunately it comes back quickly, typically within the first six months. Dr. Chapin? I think it's inevitable that there's going to be a recurrence when you see sarcomatoid like Dr. Crom says. I know you're presenting some of that data today but I think it's pretty much when? The tumor is already inside her body right? The surgical margin is positive so specifically this will come back. So the good news is I just saw this lady in clinic last week and she's now one year out and no evidence of the current disease. Good for her. So far so good. Okay, here's a 78-year-old with an incident on renal mass. She has a history of breast cancer and the mass was discovered during her surveillance for breast cancer. She has some significant history. Hypertension, diabetes, hypothyroidism, atrial fibrillation, depression. You can see the medications that she's currently taking. She has a negative metastatic workup. Her labs are within normal limits and she has a GFR of 50. And you can see she has a local localized renal mass involving the anterior aspect of her right kidney. So briefly let's go down the line. What do you recommend for this patient? So she has no metastatic disease. No metastatic disease. This is a small SRM, small renal mass. She has 78 and multiple comorbidities. This is a patient I would follow surveillance. Now I understand my colleagues to the left of me here. Well, the surgeons will say let's biopsy because the patient wants to know. I would not biopsy. It's a small mass and I would just follow her expectantly. I will enroll her on Dr. Martin's surveillance trial. It does not mandate a biopsy. But if it mandates a biopsy it will do the biopsy. But I would definitely offer a surveillance. Okay, Dr. Gao, briefly. I would agree. I would send the patient directly to Dr. Martin. Okay. Would you do a biopsy or no? You know, with her age and the comorbidities I would not. You would not. Dr. Chapin? Biopsy and surveillance if the patient refused, robotic portion. Wait a minute. So you want to do a robotic partial? No, no. Biopsy and surveillance would be my first choice. If the patient refused surveillance I would do a robotic partial. And the surveillance would be regardless of what the biopsy shows? Yeah, for the most part. I still agree because I agree with Dr. Martin and if it was me, I'd want to know. So biopsy is an option. They don't have to do a biopsy but if it was me as the patient, I'd want to know what I had in me. I mean if it came back as a grade 3 tumor, maybe it would change my mind. If it came back as a benign, maybe it would be less frequent imaging but I'd want to know what it was. Okay, Dr. Crom. I would recommend surveillance without a biopsy and then without the biopsy part for two reasons. Number one, she has atrial fibrillation is on anti-coagulation so I don't want to take her off the anti-coagulation to do a biopsy and then we know with the biopsy the grade is not very accurate so it's a hit or miss 50% of time. Biopsy is good to tell us the histology if it's cancer or not or what type of cancer but grade-wise it's not as reliable so I would just observe the patient. Okay, Dr. Matin. The option of biopsy is there and it's really a toss up for the patient. You're not worried about atrial fibrillation. We operate on those patients all the time off anti-coagulation so that's not an issue. I think that Brian makes a good point. He showed that it's an oncocytoma. You know, I would be very comfortable following her much less stringently and which is a benefit for her. She underwent a biopsy which showed an oncocytoma and she's currently being followed. So, moving on, this is a 59-year-old white male who presents with abdominal mass. It's palpable. No urologic symptoms performance that is zero. Had an 8-pound weight loss. All labs within normal limits. MRI of the brain on a negative. You can see a locally advanced tumor involving the left kidney here. Again, locally advanced tumor involving the left kidney. Can you go back to your first slide real quick? Maybe a question of a tumor. Yeah, just the presentation. Okay, weight loss. Okay, I'm sorry. Go on. So there's the locally advanced tumor involving the left kidney and evidence of pulmonary metastases. You can see a spot here. You can see a spot here. You can see a spot here. So would you offer this patient side-reductive nephrectomy? Yes or no? Let's just go down the line. Dr. Tenir? Yes. Dr. Gao? Yes, absolutely. Dr. Yes, and all three of us. No one would offer him pre-surgical therapy? Not all trial. Okay, suppose you had a trial. Would you offer him that? Yeah. Okay, so I'm going to let you in on a little secret. The case is going to turn out very well because actually this patient that we're talking about right now is in this room. Okay, so he's going to have a good result regardless. He enrolled in the synidine pre-surgical trial. He had a biopsy of his lung lesion and revealed metastatic clear cell renal cell carcinoma and he started on synidine. So the pre-surgical trial was where patients received two courses of systemic therapy. Those patients that had stable disease or responded went on to have side-reductive nephrectomy. Those patients that progressed typically we did not offer them surgery. They would instead go on to receive some sort of alternative therapy. And here's the response that he had. He had a fairly good response to it. You can see the sort of central necrosis in the tumor. There's a local extension into some of the retroperitoneal musculature here. And he had basically stable disease, maybe a slight progression in his lung metastases, but still demonstrating a good performance status. So he's got basically stable disease, maybe a little bit of progression in the lung. What do you want to do? Let's go down the line. Do you continue synidinib? Do you take the side-reductive nephrectomy and then continue synidinib? Do you switch to inhibitors, either Everlimus or Temsarylimus? Do you switch to Exitinib? Or do you do the side-reductive nephrectomy and then change the TKI post-op? Dr. Tenir, quickly. I would proceed with the side-reductive nephrectomy and then restage him post-operative. I mean the protocol, that was the spirit of the protocol. Patients after two cycles of synidinib, if they have stable disease or have responded, will proceed on having side-reductive nephrectomy with restaging post-op. If their disease is still stable or minor progression, then they can continue with synidinib. Okay, Dr. Gao. Initially I would not treat this patient, just because a small portion of patients after side-reductive therapy actually have shrinkage of the metastasis. So if he is one of these patients, I will just continue to follow him. However, if he has disease progression, you know, he had very good response to synidinib before surgery. So I would start him on synidinib again if he has disease progression. Drs. Chapin, Garam, Matin, any different thoughts? Number two, I mean the pictures you showed didn't show progressive disease, just showed stable disease for the chest. So I would follow the protocol and do the side-reductive followed by anything different, guys? Number two. So overall assessment was there was slight progression of disease in the lung, but the primary did have a response that you saw. I still had an excellent performance status, so he's taken to the operating room and he underwent a left-radical nephrectomy. He was noted at the time of surgery to have metastasis to the right adrenal, which was resected. And also a diaphragmatic nodule, which revealed metastatic clear cell renal cell carcinoma involving fibromuscular tissue, and you could see that he had a locally advanced tumor involving the left kidney. So you didn't monitor it under an elective? Yeah, I'm reading that. I'm actually... Yeah, we left it. I did this with you, I believe. We just did the mass. I think we left the left adrenal because of the right adrenal mass. Because it says there's surgery left adrenal. No, we just did it. We did a partial adrenal left. We left the adrenal tissue behind. We left the adrenal tissue behind. Post-operatively, he had a superficial wound infection and a psoas abscess that required drainage and antibiotics, and systemic therapy was actually delayed for four months because of the complications associated with surgery. But his disease, thankfully, progressed slowly and he was started on Everolimus. And as I say, he currently is president at this meeting, quite well. Let's do this case. This is a 62-year-old white male with a history of blood in the urine. He has really no significant past medical history. He's got a locally advanced tumor involving his right kidney. You can see it there. And also has bilateral pulmonary nodules. He's got some anemia. He's got an elevated LDH. All his other labs are within normal limits. His bone scan and MRI are negative for all the other labs. So Dr. Gao, what would be your approach to this patient? You know, of course, we need to know the diagnosis of this patient first. So what are you going to do? Sorry, did he have meds to anywhere else? There's bilateral pulmonary nodules locally advanced, right primary tumor and no other evidence of metastatic disease. What are you going to do? I mean, I would still do biopsy to make sure the diagnosis. Okay, what would you biopsy? Biopsy the tumor, the kidney tumor. You biopsy the kidney tumor? Okay, Dr. Taneer, what would you do? I think the concerns here, obviously the reason you're putting this case is there is high serum LDH, which we said, you know, for the audience this is lactate dehydrogenase. It's a measure of tumor burden when it's higher than the upper limit of normal. And some studies show that it is important when it's more than one and a half times upper limit of normal. So in our lab at Amgenison the upper limit normal for LDH is 618. So this is more than one and a half times above the upper limit of normal. So that's a prognostic factor that is an associated negatively with survival. The other thing is anemia. So if you look at the case here you have a patient who has advanced disease with poorest features because he's presenting with advanced disease already at the time of initial diagnosis. He has anemia and he has this high serum LDH. However the bulk of his disease the burden of his disease is in the kidney. So in this patient I would proceed and take the kidney out. I would do cytroductive nephrectomy because to remove the bulk of disease and it's very possible that post removal of this kidney mass that the hemoglobin and the LDH will improve. And then I would treat him post-operatively of course we will know then what the histology is and the histology will guide us in terms of what systemic therapy will offer him. If he has clear cell he's young 62 is relatively young as I said and he has a good organ function and he has no comorbid illnesses then I would offer him high dose interleukin-2 as the curative therapy that we have still right now. If he is not accounted for high dose interleukin-2 then he can get enrolled on one of our trials and he would be if it's clear cell he would be eligible for to enroll on the start trial. So you would not do a biopsy ahead of time you would just send him for surgery? Yes, I think in this particular case like I said I think the bulk disease is in the kidney I would not, it doesn't have what I believe are relative contraindication to upfront nephrectomy and that's performance status of 2 or worse and it's not, I think his PS is 0 or 1 you said. And he does not have brain mess, does not have multiple bone mess, does not have liver mess. So these are the criteria that I use and we both use to decide if we're going to do systemic therapy upfront. He doesn't have as I said brain bone liver he has good performance status then I think surgery is the way to go without biopsy upfront. Okay, Dr. Chapin what are you going to do? I guess I would ask Dr. De Nere a question about his response and if a biopsy were to show papillary or chromophob would you still recommend the seroid nephrectomy in this patient? Yes because again the bulk of the disease is in the kidney even if it isn't a variant histology as you're saying papillary or chromophob. More reason actually for me to do the nephrectomy would be that these other histologies don't have as many systemic therapy options as it is with clear cells. So more reason to do surgery. And so I mean given that answer I typically would not biopsy of this mass unless the person was eligible for pre-op or pre-surgical clinical trial because regardless of the finding you're going to take the kidney out especially in the setting of limited meds to the lung so I would not do a biopsy I would go right to the side of reductive. So I mean certainly this tumor doesn't look like a medullary Casinoma but what if you know if it looks like a renal medullary Casinoma you probably want to know the diagnosis first right? Well I think I'll obviously you can make diagnosis as the patient walks into the clinic before you even look at any scans he's not African-American doesn't have sickle cell trait he's 62 those are not criteria for sickle cell sickle cell will be somebody with sickle trait and with a young age so and blood? Yes sickle cell trait so I mean mostly mostly not African-Americans. Dr. Karam I would choose number three and you would not do a biopsy? No be the ultimate biopsy. Okay Dr. Matin anything different? No. Patient number one said reductive nephrectomy there's a pathology T3A N01 clear cell from his grade four and he shows up six weeks later with modest progression of their pulmonary metastases so Dr. Tanir. Hydrozyl 2 as I said so you would offer the patient Hydrozyl 2 that would be your upfront choice? If again postoperatively the kidney function is good the kidney function is good. Dr. Dao? Yeah you know you want to make sure all the organ functions are okay lung function, heart function, kidney function if it's okay he's relatively young certainly you can talk to the patient about Hydrozyl 2. What would be your recommendation or would that be your recommendation or would you recommend something different? Yeah that would be the first one because actually I always talk to my relatively healthier patients about Hydrozyl 2 therapy even though the response rate is low but that's the only chance. What is the response rate? So the overall response rate is about over 20 percent but the complete response rate is less than 7 percent partial response rate is about 15 percent so if he can achieve complete response rate the chance for him to live up to 10 years will be about 80 percent But his chances of doing that are about 6 in 100 right? That's right so it will be like 7 percent times 90 percent so that would be 5 to 6 percent. Dr. Chapin your thoughts? I mean after extensive counseling I would consider recommending IELT to the patients need to know what they're getting into with that though but I do agree it's the only way that you can potentially have prolonged, durable survivals and cures with this. Okay Dr. Kron? Typically I would refer the patient to our colleagues from medical oncology but IELT sounds like a reasonable approach and we can always give TKI's after IELT when we can't really do it the other way but I wanted to ask Dr. Gao and Dr. Taneer is there any age limit let's say if the patients organs are functioning fine is there any age cut off where you would be more nervous giving IELT? It is more important than age is physiologically age. So if the patient is 70 and is a fit then that's fine. So there's no specific age cut off there? Well obviously we don't give high dosage to people who are 75 and older I think the the oldest patient I know has received high dosage was 75 so beyond that even if they're fit they're not going to be able to tolerate therapy and receive the adequate number of doses so it's unlikely that the therapy is going to benefit them if they only get 3-4 doses instead of you know 8-9 doses per cycle. So I think 75 up to 75 if they're really fit otherwise it's 70 years and they are younger. Yeah they also have all this it's sort of like you know pre-op evaluation you have to go through all this evaluation for organ function such as you know heart function, lung function you have to do a lung function test and if the patient you can just look at the patient you can tell you know whether this patient is going to be okay or not and then you're confirmed with all this objective studies if everything fits well together yeah you go ahead and do it. Dr. Matee? Yeah I mean you know the patient's going to have to make a choice there with taking the chance with IL-2 and the risks associated with it versus something that's you know one of the more modern agents. I think the other thing that I just want to mention is we have a trial that's currently not yet approved but it sort of bridges the gap a little bit with immunotherapy and allows side-reductive nephrectomy but it's actually one where we take patients to get one of their metastases and then shortly thereafter follow it up with one of the agents that Dr. Gau spoke with you about one of the immunotherapy agents. The idea there is that the immunotherapy agents by themselves even though they have some response it hasn't been as great as we think but when you combine it with something that can prime the immune system and set up an inflammatory response that maybe you can really heighten that so that protocol when it opens is approved by our ethics board but the idea there is that we ablate it give them the systemic immunotherapy for a couple of months and then patients come in for side-reductive nephrectomy and then as long as they're doing well they actually continue getting the immunotherapy So Surin on that note what sites are you considering for ablation bone only or are you doing also lung and liver? Yeah so basically anything that interventionalists feel like they can do and as you know they've gotten pretty talented and safe so they can do the lung they can do the lung fairly safely they have good experience with that they have tremendous experience with treating bone lesions they can do soft tissue sites if there's a tumor in the other kidney we could always do that also as part of getting some local control and they're doing liver as well and potentially liver I mean that I think we need to think about there's no specific criteria for that but we certainly would you know the way it's set up is that the urologist interventionalist and medical oncologist would have to be in agreement Have we decided if it is cryo or RFA? Cryo, cryotherapy Cryo So we always laugh about this prior to 2006 when all we had was interleukin 2 and the medical oncologist used to say all we have is this lousy interleukin 2 it doesn't work on anybody the response rates are low and then we get all these new agents approved and then you have them on a panel you show them a case and you ask them what they're looking to Anyway that's our last case and I want to thank the panel for participating in this exercise and I guess I'll one more time ask the audience if you had any questions that needed to be answered Thank you Chris by the way My pleasure I heard a mention about kidney cancer spreading to other organs invading other organs and like nodules in a lung how do you differentiate between this kidney cancer that is spread and lung cancer what's the difference between the two I'll answer first typically when kidney cancer spreads it will spread to multiple sites it's rare to spread to one solitary site that's the first clue secondly when it does spread to that site it typically will have multiple nodules as opposed to just one so if you have a patient who has a locally advanced kidney tumor and multiple bilateral pulmonary nodules it's not lung cancer it's kidney cancer I mean you don't need a biopsy for that but if you have a patient who has a locally advanced kidney tumor and a solitary lung nodule if it has any sort of atypical appearances to it you might want to do a biopsy of that lung nodule to prove that it's metastatic kidney cancer or prove that it's a primary lung cancer so it's really the clinical scenario that represents a primary tumor of the lung versus a metastasis from the kidney usually the lung cancer if the cancer started in the lung has a little different radiographic appearance than kidney cancer spreading to the lungs or any other cancer that's spread to the lungs but you're right it could be that the patient can have two and in fact sometimes we have patients who have two, three or four and it just depends on our suspicion when we look at the scans if we really suspect that we are dealing with now a new cancer we will go ahead and biopsy it I mean I have several patients who have kidney cancer and lung cancer I'm treating in fact a person right now who has both kidney cancer that he's had it for six years that I've been treating him with and then a year ago something didn't look right to me on the CAT scan of his chest and I suspect this was a new cancer that arising in the lung so we biopsyed the lung and it was sure enough square mesocarcinoma of the lung that was just beginning in the right upper lobe and we treated it with radiation so yes we need to be on the lookout or our index of suspicion should be high to say this does not look like it is kidney cancer that's spread to the lung but something else and we biopsy it is it better to have kidney cancer that's spread to a lung compared to having lung cancer or kidney cancer that's spread to a liver compared to liver cancer it depends on the type of lung cancer and liver cancer and it depends on whether these cancers if they if lung cancer is metastasized already metastasized that can be challenging to treat and incurable even though we have systemic therapy options now for lung cancer or liver cancer so I think obviously it's not good to have cancer that's spread to any organ we don't want to do that we don't want to see that but I think there are more options of treatment for a patient with kidney cancer that's spread to the liver and lungs then there are for patients with say primary liver cancer or lung cancer that's spread to liver or other organs okay thank you I would also comment that the reverse is also true you do have tumors that metastasize from other sites to the kidney you could have melanoma that has spread to the kidney breast cancer was one of the topics today that we were reason why some of us were looking at biopsy because we were concerned maybe the breast cancer had metastasized to the kidney it's still breast cancer that's now in the kidney not kidney cancer just because of its location but the origin is what we describe it from so I just wanted to make a couple of comments so over 90% of patients with lung cancer actually are smokers so you can just ask about the smoking history so that will give you another clue the second one to answer your question about which type of cancer will be better so it really depends upon the stage of the cancer so just like kidney cancer if it's at early stage lung cancer is also very easy to treat you can just do biopsy other do surgery and then you can have better outcome of course once they progress to metastatic stage they are both pretty bad okay again we can't thank you enough for coming we hope that you found this informative and somewhat entertaining at least the food was good and I'm going to apologize in advance I have a plane to catch so I'm going to dash on out of here so I'm not ignoring you or running away I just have a plane I have to catch but some of my colleagues will stick around if you have questions that you want to ask them personally and we hopefully will see all of you and even more of you next year thanks very much