 Good morning everyone thanks for being here today and I would like to thank Chris and Kerry for inviting me to give a lecture again today. I think this is my seventh year and it's always a pleasure to be here. So my job is to talk to you about the management of locally advanced kidney cancer and then this will be practically four different talks in one. I'll talk very briefly about lymph node dissection, about the tumor in the vein and the vena cava and also about adjuvant and neo adjuvant therapy. These are my disclosures and this is the outline of the talk as I just mentioned and just some basic statistics in the United States last year it was expected that we would have about 60,000 patients affected by kidney tumors and the vast majority of these are renal cell carcinomas or what we call kidney cancers and there was about 14,000 deaths expected last year from this disease. Globally this is the statistic from 2013 the incidence is almost 300,000 patients affected by kidney cancer so it's not a small number at all and as you can see also the number of deaths is about a third of the patients. So this is kind of the background that we're working with here and in general most patients thankfully at diagnosis are stages 1 to 3 and as you can see about 20 to 40% of these patients although they initially had no spread elsewhere they might spread in the future and that's why it's important to do follow-up after surgery with imaging. About 20 to 25% of our patients do come to our clinic with metastasis already so this is what we call a stage 4 disease and the histology is simply what the tumor looks like or what's the type of kidney cancer. Kidney cancer is not simply one disease it's multiple subtypes that are under the umbrella of kidney cancer. As you could see here the vast majority are clear cell histology or the clear cell type that's about three quarters of our patients. The second most common is papillary and the third most common is chromophobe and you could see a small minority of other cancers like the renal medullary carcinoma which is an extremely aggressive tumor same thing with collecting duct and also translocation kidney cancer. Now when we talk about staging how did we come up with these stages 1 2 3 4 so there's an acronym it's TNM. T is for tumor so T1 is a localized tumor that's less than 7 centimeters T2 is still localized but it's larger than 7 centimeters. When you look at T3 and this is really what my talk is going to be about these are tumors that now are invading the fat around the kidney the fat within the kidney or in the vein of the kidney itself and T4 is when the tumor invades directly into other organs. This is not true metastasis this is direct invasion so when now we look at the end stage N is for nodes for lymph nodes if you have no lymph nodes effective affected your N0 and if you have lymph nodes affected your N1 and for the M stage M is for metastasis so if you have metastatic disease or spread that's considered M1 and part of this will be covered by Dr. Wood and my colleagues from medical oncology later on during the day. So when you combine all these things together you will have the stage here in Roman numerals and my focus would be on a stage 3 which is T3 or tumors invading into the fat around the kidney or within it or the vein or N1 which are patients who have positive lymph nodes. The grade of the tumor and these are things you might see on the pathology report the grade is just how aggressive or how ugly the cells look like under the microscope and if you go from left to right on the slide you go from grade one which is the lowest and the cells look kind of more or less homogeneous they look kind of nicer when you compare them to the one on the far right which is a great for tumor and these are the very aggressive types of tumors. So these are the different disease states or entities that we you know focus on the earlier one is the localized that Dr. Matin covered these are the situations where we can do surveillance or ablation or partial infractomy the next step would be the locally advanced tumors and these the patients who have a locally advanced tumor are usually treated with radical infractomy and that you know majority of the cases the locally recurrent and the metastatic tumors are even more advanced but I will not cover them during this talk so again my focus will be on the locally advanced tumors so the first topic would be kidney cancer that has gone to the vein of the kidney so we call that a venous thrombus or a tumor inside the vein and that could be inside the renal vein and that could ultimately travel and what we call the IVC or the inferior vena cava that's the vein that takes all the blood basically back to your heart from below the level of the heart and on this picture you can see over here on the left side this is the heart and you can see the tumor all the way into the heart and again this is not a metastasis this is a direct spread from the kidney all the way into the heart and you could see it here on the left kidney going from the left kidney to the vein all the way into the vena cava which is this structure here and I'll review our experience here in a second at MD Anderson but in general this is the classification it is considered a T3 and the higher it is the higher the classification is so T3C is the tumor has already reached the heart or the atrium this is our experience and this was updated several years ago at the time when we last looked at our data we had 600 patients that were treated with kidney cancer and had tumor invading into the vein of the kidney as you could see here the the median or the average age of our patients in this setting is about 60 years follow-up was relatively short about two years the tumors are not small they're about 10 centimeters on average and most of our patients had clear cell and about half of our patients had no involved nodes and no metastatic disease so these are locally advanced without spread and as expected most of these most of these patients had tumor in the renal vein and the less a number of patients had tumor in the vena cava itself and the minority thankfully had tumor all the way into the atrium or into the heart the surgery is not a simple surgery it's a very serious surgery that we do as a team effort and I'll comment on that later the blood loss is about the leader on average the surgery time is about three hours on average hospital stay is about a week there are some potential complications about a quarter of the patients have some sort of a complication in the first month after surgery the surgery is not without mortality and we see that in about 2% of our patients so it is a very serious operation that again we do it as a team effort to try to get the best outcomes for our patients and we have done several studies and from other centers as well we know or we can potentially predict which patients are not going to do well after surgery so patients who have the non-clear cell types of histology in general they do worse with this type of disease when it's gone to the vein if you have a very high-grade tumor like the one I showed you if you remember on that slide on the right if you have sarcomatoid disease and the kidney that's also a very bad indicator if you have tumor invading the lymph nodes it's also a poor prognostic indicator meaning that if you have one or more of these factors with tumor in the vein usually there's poor or worse survivals compared to if you don't have them so the take-home message for this part of the talk for the thrombus is that really surgery is still the main therapy in the setting it can provide you know durable survival and we have the survival in our patients who don't have disease elsewhere is about five and a half to six years on average after surgery we do it as a multi-disciplinary team so we work with thoracic surgeons or with vascular surgeons to try to get the best outcomes and the complete resection for our patients it is a technically demanding operation but with our experience here and in other major medical centers the outcomes can are as good as possible and these are the factors that I mentioned you that can predict a worse outcome in our patients so let's move to lymph node dissection and Dr. Matin mentioned the role of lymph node dissection in kidney cancer and what Dr. Matin was mentioning more was this is doing lymph node dissection and patients whose lymph nodes look normal on CT scan and look normal during the operation what I will focus on here are patients who have lymph nodes that are suspicious on CT scan and suspicious during the operation so it's a very different clinical entity in general we know that if patients have presence of lymph nodes it's an indicator also f worse survival as you could see here this is the right kidney this is the left kidney and this is just a very large you know clump of lymph nodes here so these are this is considered the patient with a positive lymph node and this is what I will focus on so we looked at our experience about six years ago and we looked at our database of patients who had positive lymph nodes but without any other sign of disease outside of the kidney so there was no spread into the lung or the liver or the bone just the kidney itself and the lymph nodes and that patient population is actually very small as you could see here only about 2.7 percent of the patients fall into this category so keep those numbers in mind and what we found is that these patients when they had surgery to remove the kidney and to clean out the lymph nodes completely and again these are patients who we knew they had affected lymph nodes the survival is about 37 percent so about a third of the patients can potentially be cured with an aggressive surgery to remove the tumor and the lymph nodes in the absence of disease elsewhere so you know you can look at this as glass have full or glass empty but this is a third of patients who we can you know help achieve long-term survival just by purely by surgery and I think this is a good outcome in the small patient population again this was about 2.7 percent of our patients only this is a just an example of a patient this is a large right kidney tumor you could see here a lot of lymph nodes and one can say well this is very aggressive we're not going to do surgery we're just going to give up but since this patient did not have any spread elsewhere we were encouraged to take this patient to surgery obviously offered him different options but this was the preferred option for this particular patient and we removed the tumor as you could see here and this is the surgery basically after everything was removed this is where the tumor used to live this is the the vena cava this is what I mentioned earlier where the tumor can go and invade directly in it this is the aorta over here and you could see here these vessels normally don't look like this they're usually covered by lymph nodes so for this patient we removed completely all the lymph nodes from around these blood vessels in order to achieve complete resection so the take home message for this patient population and again these are patients who we know have positive lymph nodes we can help some of these patients with surgery the patients who do better are the ones who have the papillary subtype which is the second most common one the patients who we can achieve complete removal of all affected lymph nodes these patients will do better the less the number of affected lymph nodes the better the outcome and that makes sense if the patient does not have sarcomatoid features this patient will do better and as you could see this recurrent theme of sarcomatoid is bad sarcomatoid is bad so it's something that we see in about 5% of our patients and if the patient does not have it it's usually better and patients who have a good performance status meaning patients that are up and about they're walking they're functioning otherwise normally they're going to work in general these patients do better with this kind of surgery so I'll move to the third topic which is the neo adjuvant and then the adjuvant therapy so this is basically we're talking about surgery plus some additional systemic therapy which could be a pill or it could be an IV injection and just to define the two terms so we have neo adjuvant and neo here means something that's done before as you could see here we're giving a certain drug I'm just gonna call it drug a initially and then we do an effrectomy or the kidney surgery and then we observe so by definition we call this neo adjuvant therapy now adjuvant therapy is when we do the kidney surgery first and then the patient now has no disease but the question that a lot of our patients ask well doctor can I do something to decrease my risk of recurrence and then giving a drug afterwards that's called adjuvant therapy or assisting in order to decrease the risk of recurrence and I'll discuss this in a few minutes so let's look at neo adjuvant therapy so why would we want to give a drug before surgery why don't we just take our patient to surgery and just be done with it so there are some reasons why with sometimes we do these kinds of approaches one would be to try to shrink the tumor before surgery and I'll discuss it in more detail to make it easier to operate sometimes we have to preserve the kidney and the tumor is so large we cannot so we give these drugs to try to shrink the tumor and make the surgery feasible and make preserving the kidney feasible sometimes we look at the scan and we say we cannot remove this tumor there's no way we can resect it so we give sometimes these drugs to try to shrink the tumor and make the surgery possible the IVC thrombus that I mentioned earlier when the tumor goes into the vein some authors have tried to use these drugs to shrink it to make it an easier operation and to make it less evasive operation but this has not worked out very well and I'll go through the data in a few minutes here and sometimes we do it in our patients who have metastatic disease to see if the patient responds well to therapy and they are functioning well then we take our patients to surgery and we call this a litmus test basically we're trying to see if the patient is going to do well with surgery and sometimes we spare the patients an unnecessary operation by doing this kind of approach first so there are several things we need to keep in mind when we're thinking about new adjuvant therapy you know what kind of what kind of tumor it is what kind of drug we're gonna give how much for how long and when to stop it before surgery so the first question is can it shrink tumors and some of these drugs can and these are just different studies that I've listed here but as you could see here with these three drugs exotinibazopinibinsinitinib these are all oral drugs we can achieve tumor shrinkage in about you know 25% decrease in diameter and these are studies mostly done in patients with clear cell histology again the most common type so we know it can shrink tumors but it doesn't shrink them for every single patient and this is a study that we conducted here this was a study that Dr. Wood and I did and published a few years ago that we had patients who had clear cell kidney cancer and we gave them this drug for three months and then we did an operation and this is the outcomes of the study I'll show him here most of the patients as you can see had T3 and again if you remember this is locally advanced stage three kidney cancer most of the patients had high grade tumors again grade three and four and this is what we found partial response in about half the patients and partial response meaning a tumor shrink by more than 30% stable disease meaning it did not shrink all the way to 30% the good news is that no patient had progression of their disease so nobody was taking the drug and the tumor grew while on the drug and one patient we had stopped therapy because of adverse events or side effects from the drug itself and I'll show you just as an example of one patient that this was initial this you see a large tumor on the left kidney and after three months of therapy this is how the tumor became but again keep in mind we don't see this in every single patient and at this moment we cannot predict which patient is going to behave like this and which patient is not going to respond to this drug and that's why we're doing a lot of studies right now to try to predict which patients are going to respond to these therapies so that we can avoid giving these drugs to patients who we know they're not going to respond to so this is all research in action right now so next thing is can we change unresectable or patients who cannot have surgery and make them have surgery hopefully for benefit and there are several studies that I'll go through very quickly these are small retrospective studies in general this is from our colleagues at Cleveland Clinic and after receiving the drug four out of 90 patients were able to have surgery this is a study from the Netherlands three out of ten patients were able to have surgery after receiving the drug and this was a prospective study and ultimately about 45 percent were able to have surgery after receiving the drug again the the main issue here is that we don't know which patient is going to respond to these drugs and we won't know until the patient actually received the drug first so now the other question is can we change a complete or radical nephrectomy to a partial nephrectomy and there are some studies that have shown it is possible in some patients including our study where we were able to do five out of 24 surgeries in a partial nephrectomy instead of a complete or radical nephrectomy and this has been studied by three other centers as well including Cleveland Clinic and UC San Diego so this is an example of a patient that I saw in my clinic our patient had one kidney only the left kidney and just presented suddenly with a 13 centimeter tumor in that kidney this is the tumor it's practically replacing most of the kidney so this is a patient that the option really is to just take out the entire kidney this was not possible to save the kidney in this particular setting so we offered him based on our studies why don't we do a biopsy if it's clear cell we can give you the drug that we used in our study and we did that and we referred the patient to our colleagues in medical oncology and the patient received a therapy in oral therapy for several months and this is after seven months of this drug the tumor shrank you know by half the size so this patient basically we took him to surgery and we did the partial nephrectomy and we're able to save his kidney and got the tumor with clean margins unfortunately this does not happen for every single patient but for this particular patient I think he derived great benefit and was able to be off dialysis with this particular approach as far as the tumor thrombus again we're trying to shrink the thrombus all the way from the heart or from the vena cava back to the kidney or as low as possible there were several case reports that said you know we can do it people were excited about it but the problem is that people were not publishing all the times when they gave the drug and the tumor did not shrink they only published the good results so what we did is we decided to look at this with our colleagues from Dallas from UT Southwestern and we had 25 patients in common and we actually found that only three out of the 25 patients had shrinkage of their tumor from the vein and actually one only out of the three had shrinkage that was meaningful enough to change what kind of surgery we do so in general this is not an approach that we do in general we don't recommend giving this drug to shrink the tumor from the vein if the patient can have surgery we go immediately for surgery and several other centers have corroborated our results this is from a French group also retrospective small study but only one out of 14 patients had shrinkage of the vein tumor and this is from Southeast Asia only two out of 22 patients had shrinkage of the tumor in the vein so we know these drugs can shrink the actual kidney tumor itself and they can shrink sometimes the lymph nodes but they cannot shrink the tumor if it's inside the vein itself and then this is something that I'll briefly discuss as the litmus test and the metastatic patients and in general we use this in many different ways but one way to use it is to see if this patient might derive benefit from surgery ultimately the thing is if we give the patient a drug that we think is the best drug that we have and the tumor still grows while on that drug in general we know this patient is not going to benefit from surgery and this is what these different studies here showed as well this is using interleukin 2 therapy this is from many years ago this is using interferon therapy and also what we found or what these authors found is that if you give a drug to a patient that has metastatic disease and the tumor grows while on this drug in general this patient should not have kidney removal surgery so this is one way where we could potentially avoid putting our patients through an operation that might not be necessarily helpful as far as safety in general these drugs are safe and we have learned a lot over the years the main complication that we see is wound healing so now we are more careful about when we stop these drugs before surgery when we restart these drugs after surgery and the wound complication is actually quite low this is from our study the wound complication rate was only about 4% and in general this is really the most common complication but with appropriate management we can minimize that risk so just as a take home message for the new adjuvant therapy in general it is a safe approach but there are some potential risks of wound complications we know it can shrink the tumors but not for everybody sometimes it can help us change a complete or radical nephrectomy to a partial nephrectomy sometimes it could help us change an unresectable tumor to a resectable or surgically removable tumor it rarely changes the level of the tumor thrombus in the vein so we don't use it for that approach now the key thing to keep in mind is this is not something that we do routinely we do this either on a clinical trial or in very specific scenarios like the patient I showed you this was really the only realistic option at that point so this is not a standard for every patient that comes to clinic and it can help some patients and what we're doing research on is to try to find out which patient it's going to help before we actually give them the drug so the last topic is adjuvant therapy and as I mentioned adjuvant therapy is that patient comes to clinic there's no metastatic spread anywhere just the kidney tumor itself we take the patient to surgery we take the kidney tumor out we do a scan a month later everything looks clear and now the question is do we need to give the patient something at this moment there is no approved drug that we can give to try to minimize the risk of recurrence but this is what adjuvant therapy is there are several clinical trials that I'll go through very quickly now for the sake of time and the real or the ideal adjuvant therapy setting in my mind is that the patient should be at a very high risk of recurrence if the patient has lower risk of recurrence why should we give that patient any drug the chance of them having recurrence is very low the drug has to kill the cancer when it's very small level small microscopic level it has to have low toxicity profile because the patient will have to take the drug for usually about a year at least it should not be very expensive and it should provide a clinically meaningful outcome meaning it should help the patient live longer in general and these are the different trials but I'm not going to go through them like this but to show you the trials that have been published so far this is the assured trial and this trial Dr. Wood and Dr. Mateen participated in a few years ago and this was published in the Lancet and what basically it did it is split the patients into three different groups and the patients received you know one of these two drugs or a placebo for a year and the disease free survival meaning being alive without cancer or being alive in general did not differ between the three groups so whether you receive the drug or not did not really help this is one of the earlier trials in this arena now a subsequent trial called the S-Track used just synitinob the patients were divided into two groups one group received the drug the other one received the placebo and the results were a little bit different than the trial I just showed you so being alive without disease our disease-free survival was better when the patients received this drug however when we looked at the overall survival meaning just being alive in general the drug did not help prolong the patient's lifespan so this is something that we have to keep in mind if this drug gets approved how we talk to our patients about it and this is subject to a lot of debates right now in the field this is another trial using immunotherapy and this is a specific antibody to a molecule called G250 also did not show any benefit in survival as well so this was recently published just last year so there are some recently completed trials that are awaited we're waiting for their publication and I'll just go through their titles and what drug they are this is called the atlas trial using exitinib to try to see if it helps decrease recurrences we don't have the results just yet the everest trial using a drug called everolimus it's an oral drug as well we're waiting for the results this one is called a source trial using another drug called seraphim it's also an oral drug and we're waiting on the results as well the protect trial was recently completed and it should be coming out soon it looks like the results are not going to be significant meaning whether you take the drug or not your survival is the same so there's no need to give the drug but we're waiting on the official release of the data and the presentations and this is using a drug called pizopinib the current trials right now are mostly focused on the new immunotherapies so this is a trial that we are about to start here hopefully in the next couple of months using an immunotherapy called atasalizumab and the patients will be divided into two groups patients either take the drug or they don't which not taking the drug is the standard of care at this point at this point so this is a multi institutional multinational clinical trial another trial called prosper that's a cooperative trial in the u.s. is using a different drug called novolumab and it includes a new adjuvant portion similar to what I've described earlier these just got started just a couple of months ago so we're barely just accruing to these trials there are some other trials that are being prepared right now using different agents that I've mentioned here so for the take-home messages for adjuvant therapy it's very important to know at this point there is no approved drug that can be used for adjuvant therapy so at this point when we see a patient in our clinic if we resected all their cancer and their cancer free now we either watch the patient with repeated imaging or we enroll them on a clinical trial if they would like to do so at this point there's only one trial that showed benefit and disease freeze revival but not an overall survival and we certainly need to do deeper analysis in these trials to gain more information and we definitely would like to encourage our patients to participate in clinical trials whenever they're available I would like to acknowledge all our patients who trust us with their lives to take care of them and without our patients we wouldn't be here in this center and also acknowledge my colleagues and mentors and collaborators without which a lot of this work would not have been possible then thank you very much for your attention do you have any time for questions Chris or any questions well we can take questions offline if you all want in the break so thanks very much for being here this morning