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