Transcript for:
Diagnosis and Management of Kidney Cancer

good morning everyone welcome to the course on diagnosis and management of localized locally advanced and advanced kidney cancer i'm very thrilled to uh welcome my uh to the people here in the audience and they tell me a huge group of people watching this virtual uh we're thrilled to have you and i'm thrilled also to have my colleagues dr martin ball from the national cancer institute i'm going to talk about genetics of kidney cancer and about how that affects your management your surgical management of patients with kidney cancer dr ball is going to talk about many of the the advanced aspects of surgical management of kidney cancer we're very thrilled to have dr david mcdermott and one of the leaders in the field from beth israel deaconess medical center dana farver harvard cancer center in boston obviously is going to talk about some very exciting new data on advance management of advanced forms of kidney cancer and he's going to be primarily focusing on clear cell renal cancer and we're also very very happy to have another leading expert in the world on this dr rahm cervasin again from the national cancer institute he's a medical oncologist as is dr mcdermott uh and who's going to talk to us about management of non-clear kidney cancers advance and also going to give you some very exciting up-to-date information on drugs we may use to treat localized disease in patients with vhl targeting if two so we're going to hear about those things and i'm going to start then are we doing the questions now am i going into my talk okay just keep going okay all right okay here we go all right so we're going to uh do a poll test and we'll do this before the session we'll look at questions and then we'll do it after as well and the way you respond to this is with your cell phone you text to and anybody who's got any questions she's here in the back in the blue shirt can help you with this you text to two two three three three that's two two three three three and you put in the body the message k johnson o eight o that's k johnson o eight o in the text and you'll get back the poll okay all right so we'll and she'll she can help anybody just raise your hand she'll help anybody who's not not square but this time most people are pretty cool with it so i'll just give you a little quickie test here so this is just a just a a test to see if you can get the system to work and what do you like most about new orleans you know a aua of course b uh creole cajun food c the french quarter or d uh bourbon street i'd go for d what uh what what we have some results coming in here uh so we'll go ahead and go through this so here are the most people like creole and cajun food well my mom would love that being from new orleans so uh okay so i think you've got the system pretty well worked out so um okay so now we're going to go to the actual pre-test and we're going to do some questions here and the first one is the recommended surgical management of a 26 year old patient with vhl von hippel lindau with bilateral multifocal clear cell renal cell carcinoma the largest which is in the right kidney is two centimeters so patient vhl clear cell largest tumor is two centimeters so what do you mean how do you manage that vhl clear two centimeters right nephrectomy bilateral nephrectomy these people get tumors on both sides right partial nephrectomy or active surveillance okay so that'll be question pretest one okay we'll go to question number two all right now tumor and nucleation so you've got a patient with renal cancer tumor enucleation as opposed to wide excision partial nephrectomy is best suited for a patient with multiple comorbidities and a small renal mass so tumor nucleation just take out the tumor what's it best for multiple comorbidities a small renal mass b a large renal mass where biopsy suggests high grade features multiple renal tumors or d and infiltrative renal mass okay a nucleation versus wide on the partial how would you handle that surgically okay all right so we'll go to the next test number three all right so this is a good one lymphadenectomy for rcc is best indicated in which of the following scenarios so lymphadenex uh when do i do lymphaden good question for all patients with c2 or greater tumors at the time of radical nephrectomy okay got that with renal sinus fat invasion c for a patient with enlarged inner aerital node or d for a patient with biopsy proven papillary type 1 rcc so when when when do we recommend lymphadenectomy all patients tc radical nephrectomy enlarged nodes or type 1 pap the all right let's go to four okay so up front cyto reductive neffrectomy that's a good question when we see patients come to us metastatic disease up front side of cytoreductive nephrectomy is a treatment option for patients with a small volume metastatic disease all right cytorectomy small volume but okay that makes sense imdc poor risk metastatic renal cancer that'd be a good one for this low performance status metastasis involving multiple organs the patient comes to you as it makes sense to cytoreductive nephrectomy and which of these following scenarios okay all right let's go to pretest number five in patients with kidney cancer response to pd1 so that's io therapy we're seeing a whole lot of that obviously in patients one of your patients has metastatic disease response to therapy with an immunotherapy targeting the pd-1 pathway blockade you know these are a lot of these agents and very exciting have been associated with which of the following response to pd1 okay which of the following is that if we sequence it into tumor mutation burden is it those that have sarcomatoid histology sarcomatoid okay are they more likely to respond or hope and so is it if their t effector gene expression is up or the last one is the pbrm1 gene which is on chromosome 3 next to the vhl gene is that the answer number d okay okay all right so next i'm going to start with again the genetic basis of kidney cancer why this is important to you and me as urologic surgeons in our management of our patients now when we started our work on kidney cancer and three and a half decades ago kidney cancer was a single disease we treated them all the same surgically gave them all the same drugs none of which working very well we now know that kidney cancer is not kidney cancer it's made up of a number of different types of cancer that just happen to occur in this organ different histologies you can see here different clinical course responding differently to therapies and as we now know caused by different genes we now have 18 18 different genes that cause kidney cancer so kidney cancer just happens to happen in this organ 18 different types of cancer and most of what we've really learned about the genetic basis of it comes from our study the study of patients with hereditary or familial kidney cancer this is much more common than people thought and that we now know there's at least 14 different types of inherited kidney cancer that you'll be seeing in your office if you manage kidney cancer and those are the genes that cause those 14. now why do we care as urologic surgeons about the genetic basis of kidney cancer i'll tell you why because it'll make you a better surgeon and a better clinician there's no question about it so in other words and you're going to hear a lot more about this for myself dr ball and the other speakers in other words if you have a patient and you know the genetic basis of it should i do active surveillance watch this tumor there's a lot of people doing that or should we do surgery now also what kind of operation should i do robotic versus open should i nucleate you heard from we'll hear from dr ball should i go wide on my margins or a nucleate how should i do this surgery and should i do active surveillance on this or should we treat this patient if we treat and you're going to hear a lot about this from dr mcdermott dr shinovasan agents that target the vhl hiff veg that target the met pathway another cancer gene kidney cancer gene the fh pathway we'll hear about or should we give them you know these immunotherapy drugs pd1 pdi1 ctla4 we'll hear about that so we're going to talk briefly about four different types histologic types of kidney cancer and just give you a little overview a brief overview of how we might think about managing these individually that are different from each other so we'll start off with the most well-known type of inherited kidney cancer and what that's taught us about how to manage regular non-hereditary most common type of clear cell kidney cancer so we'll start with this patient 29 year old female appears to be affected with von hippel lindau she comes for initial screening she hasn't seen doctors whatever this happens all the time she does have cerebellar hemangioblastoma had surgery and now she's come to understand she has something in her kidneys how do you make that diagnosis well it's really simple and i'm going to say the same thing about all these really simple all you have to do is order a panel all right so panel of kidney cancer genes it'll have 18 or 19 genes in it and you can also throw in some dna repair genes if you want but you don't even have to remember the gene names just just get a panel all sorts of companies run these they're not that expensive insurance generally will cover it so this the disorder is called by an abnormal caused by abnormality of this gene we called the vhl gene all right and there 100 percent so far 443 families were now up to 3 43 443 we found mutation so it's a basically a very very accurate test easy to do and not that expensive anymore fortunately so this patient had positive tests for that you can see on this screen what that gene was and she has these tumors in her kidneys all right so she's got a number of that hurts you got one centimeter a couple that are two couple that are one five and one in the left kidney that's 3.5 centimeters so how do we manage that do we watch it do we operate do nephrectomy bilateracy what do we do here so we've learned over the past 37 years in managing papers with von hippel lindau and many many surgeries and surgical approaches and working on this this is always clear cell renal cancer we don't say always often in our field but this is always clear cell over the years we developed a surgical management approach where we recommend active surveillance not doing surgery active surveillance the largest tumor reaches the three centimeter threshold at which time we recommend surgical intervention in 37 years 1254 patients not yet not we made more of it as of today not yet had one patient develop metastatic disease we've had 53 of our patients develop metastatic disease but had larger tumors not one yet with three or smaller so that we recommend for this and two others i'll show you but very differently for other types of kidney cancer here she had a left robotic by dr ball left robotic partial nephrectomy 50 actually was prior to dr ball but 54 lesions were removed 33 cysts were taken out these were all isop2 so you and i would say fermin two it's now isop2 and uh patient has has done very well post-op now how do we do these procedures what do we recommend we recommend a nucleation all right now we've taken out as many as 93 tumors from a single kidney and uh one of the fellows not too long ago took out i think 51 or something but we are very careful about this and you hear about this from dr ball we do a nucleation so if we're taking out a bunch of tumors you can't take big margins on these and we've done very well with this so that's our approach for vhl clear cell vhl mutation kidney cancer so that's the first base all right so here's the second one this one has no family history has one kidney one tumor in the kidney has a 3.3 centimeter uh mass in the left kidney okay well we decided to biopsy this so he had a biopsy and then surgery had a nucleation this was a clear cell renal carcinoma vermin or isop2 in other words low-grade uh renal cell cancer and actually a good question for dr ball on this one i want to ask him this is i know what he did here but how would you manage these going forward what do you recommend to people who biopsy something they know it's clear cell maybe they even know it's the vhl mutation do you nucleate here do you go a little wider so we'll we'll get that for him during his talk and this is sporadic non-inherited uh clear cell kidney cancer vhl mutation in over 90 of these tumors now here's the third case so this one shows up sadly with a larger tumor again biopsy here showed clear cell renal carcinoma higher grade and sadly this patient presented with metastatic disease big mass in the retroperitoneum and also disease in the neck so what do you do here and we'll talk about that more when do you when do you resect when do you go after locally advanced disease and how do you think about treating these systemically and we're going to hear a lot about this but basically this pathway we and others our colleague bill kalin at harvard obviously huge in this uh have have developed described this pathway we know that the vhl gene product of the vhl gene targets something called hypoxia inducible factor you'll hear about or hif normally for degradation and when it's mutated in the cancer it can't and if goes up and that drives a bunch of things you and i know means cancer like blood vessels and local growth and all that and this provided the foundation for the development of drugs targeting clear cell kidney cancer the understanding of this pathway we now the fda has now approved nine drugs that target this pathway and we're going to tell you you're going to hear from dr cenavasin about the 10th drug that was just approved for vhl kidney cancer big studies going now with sporadic kidney cancer targeting the hif2 pathway in vhl which we think is the most critical pathway and you'll hear the work about the hif2 drug belzoodafan in patients with vhl so that's clear cell how about non-clear cell right we say clear cells about 75 of kidney cancer what about the other ones they sure seem well we sure see a lot of them so this is a patient that we saw uh had multiple tumors in both kidneys bilateral multifocal and this was type 1 papillary kidney cancer he also had a family history of kidney cancer many people in his family just kidney cancer didn't have anything else like brain or tumors or theos or something like that just had papillary kidney cancer we call this hereditary papillary renal carcinoma hbrc familial form of type 1 papillary kidney cancer well over the years this is i think now 20 27 years actually we've developed a surgical approach managing this same way as vhl but we manage these conservatively with with active surveillance until the largest tumor reaches three centimeters and again as of today we not in 27 years we've not had one patient develop metastatic disease when managing that faction we have had a number sadly come with larger tumors develop metastatic disease this is cancer but not there so that's how we recommend managing these how do you make the diagnosis again just do a panel a panel of kidney genes it's a family it's bilateral we recommend genetic testing for people who are under 46 people have bilateral multifocal and people have a family history so it's easy to remember it's easy to get the test this is one of the genes met so that's the gene for hereditary papillary renal carcinoma now how about this patient this is a 55 year old who we saw with bilateral multifocal disease he came with this and again this is one dr ball operated on you can see this patient had bilateral multifocal disease on the largest on the left is 4.8 centimeters we don't like that on the right it's four centimeters we biopsied this it was type 1 papillary renal cancer okay bmf we did it we did a panel it was negative exactly this is bilateral multifocal disease that's much more common than is uh than is a hereditary papillary we manage those the same way so he had bilateral partial nephrectomies this is a young woman who came with this large cancer it was papillary we found it to be an unusual type of kidney cancer it was actually novel when we found it and that's a t something called tfe3 kidney cancer which is a type of papillary kidney cancer when you your pathologist will stain those cells it'll come up positive for tfe3 and you if you you know if they're not sure it's kind of a funny papillary maybe clear papillary say stain for tfe3 kidney cancer and also the staining if it's a little iffy ask them to do a fish test a fish test it's easy to get it's the gold standard and it will tell you a hundred percent if this is what you call a fusion kidney cancer you might say well it sounds pretty unusual but it's not as unusual as you think also here's one we saw a 23 year old who came up from the south she's a law student and she had this two centimeter two centimeter lesion in her left kidney and she presented with positive node so this you do not do active surveillance on this is more common than you think 40 percent of kidney cancer in children and young adults a young person with kidney cancer under 46 think fusion think tfe3 or tfeb you could even see it in adults it's about 12 percent of type 2 papillary we do not recommend active surveillance here this is the last one i'm going to go over and this is this patient here oh she was 24 she had this cyst in her left kidney we weren't sure is there something else there on ct we weren't so sure we did mr and we saw this she's 24 we said oh my word she also had a skin bump cutaneous lyomyoma and she had early onset fibroids we said oh my this must be hlrcc we did germline testing it was positive another one of the tests on that panel for fh gene fumarate hydrotase she had a family history you can get cutaneous and uterine lyomyomas and kidney cancer the gene is fumarate hydrotase we need another group help characterize this this is highly effective 98 we have 764 patients with this and or 98 positive on this general germline test so how do you operate on this we went wide i mean wide on this almost all the way to the collecting system with this one it was tumor inside the cyst also it invaded through the parenchyma this is the patient we saw this guy and his family actually this is 52 year old had bilateral multifocal these small lesions you see we took this out you can see we go wide on this we looked at that and my word it had already gone through the capsule and was invading into the parenchyma if you'd done your our standard nucleation not not good you spilled these cells that's trouble this was his 17 year old daughter she shows up with this left kidney you can see there at about three o'clock in red is one lower about 6 30. these came out look at this our pathologist fell over dead she said marston you're not going to believe this this tumor this little seven millimeter tumor has gone already through the capsule and it's invaded up into the parenchyma i said don't tell me we've got a positive margin no no she's no you don't went wide on that so this is a guy came with a cyst a small tumor inside cyst positive node that spread these can spread when they're small so you don't do active surveillance this is the lady that was going to get screening on the outside we saw an 03 and then she didn't three years later she got screening they called this negative but we look real close it's easy in retrospect maybe a lesion there four years after that they called me and said hey we got one of yours over here it's over in a city near ours and yeah she had this that that 1059 nodes were positive we lost her two and a half years later so we do not do active surveillance on these and imaging every single year so what i've showed you is kidney cancer is not a single disease different histology is different clinical course caused by different genes with different clinical approaches and we use you use a precision surgical approach some you manage some you do surgery some you do a nucleation some you go wide but understanding the genetic basis of this disease will make a big difference thank you very much i'm happy to welcome to the podium dr mark ball he's looks good but he should be a little exhausted this is his third educational course at this meeting dr ball good morning everyone uh it's great to to see so many faces in person this is the the third time we've given this course but the first time in front of the live audience so it's certainly great to see some familiar faces in the audience as well pull up the slides for mark ball if you can so my task this morning is to to really talk about sort of two bookends of surgical management of of kidney cancer and that is how we do partial nephrectomy and then on the other end for advanced disease when to think about cytoreductive nephrectomy bear with us for just a moment yes we can try that is one moment folks fox all right everyone here we go okay no relevant disclosures so again how how do we think about partial nephrectomy and how do we think about cytoreductive refractomy are the are the two uh two considerations for this talk so let's start with partial nephrectomy so this is a case that i saw about 18 months ago this was a 71 year old man who was referred to us with bilateral renal masses he did have a genetic workup since he had bilateral masses but it was negative um he actually before he saw us had a biopsy of the right kidney the smaller tumor but a little more central that showed a clear cell uh rcc no firm and grade was given uh the left was not biopsied he had good renal function his creatinine was 0.9 and he had an egfr of 79. so this he was referred because um nephron sparing surgery was uh was needed for someone with bilateral renal masses so how do we think about that and when i think about um how to do a partial nephrectomy i really have my decision making along four axes when to do open versus robotic surgery when do i do a traditional transparent nail versus a retroperitoneal approach what tumors are appropriate for tumor nucleation versus maybe the more traditional wide excision and when do we need to clamp the renal hylum and when is it more advantageous not to clamp so i'll go through each one of those and then we'll come back to the case so open versus robotic i think that the biggest driver here is really surgeon experience and comfort there are and that depends a lot on your training if you have trained to do complex partial nephrectomies via an open approach that uh that's a fantastic approach to treat many renal tumors i will say though because of the increased utilization of robotics over the past decade that more and more trainees have more exposure to robotic and many programs almost exclusively robotics so because of that i think the current generation of trainees and certainly in the future we'll be doing many of these robotically another consideration is the need for cold ischemia and for a long time but there there was dogma in kidney surgery that every minute of warm ischemia counts and the 15 minutes is quantitatively better than 60 minute ischemia and i think a lot of that has um uh has really been disproven a lot of that by the seminal work from from steve campbell and the and the thought leaders at the cleveland clinic who have showed that ischemia as long as it is a reasonable amount of time in the half hour uh ballpark uh does not make a make a difference it's really more of the parenchyma of the kidney that's preserved however there still may be cases where cold ischemia could be preferable for a patient with a solitary kidney and a complex renal mass you just heard the the very nice talk from dr linehan about about the genetics of kidney cancer and of certain hereditary syndromes and we feel very strongly that patients with hlrcc or patients with sdh deficient tumors can benefit from open surgery these are aggressive tumors even when they're small they don't have normal tumor pseudo capsules and they can infiltrate widely into the normal renal parenchyma and we feel that you can do a more complete resection without the risk of maybe a tumor rupture if you had an open approach and there may be some considerations for the the patient's surgical history if they've had prior renal surgeries um there may sometimes be advantageous to approach those uh via an open approach uh we we we feel strongly that there are many cases that robotics can still be preferable but again that goes back to the comfort of the surgeon and we're at the aua so let's see what the ao a guidelines have to say guideline statement 22 at the bottom here in patients undergoing surgical excision of a renal mass a minimally invasive approach should be considered when it would not compromise oncologic functional or periodic outcomes i think it's a very uh reasonable way to think about it now how do we get to the kidney i think that the for most of us who do robotic kidney surgery the transperitoneal approach uh is probably the more comfortable probably the more default uh certainly in my training 90 percent plus where transparency kneel it's more familiar anatomy you can see the great vessels the renal hilum reflect the colon and that gives you more working space but there are certainly cases where having a retroperitoneal approach in your toolbox can be advantageous it's great for posterior tumors um and um you know for a posterior tumor it can be challenging to see the base uh unless you really flip the kidney transparently it can be a challenge for your surgical assistant to give adequate uh suction at the base of the tumor and and this is uh really ameliorated with a with an rp approach there are caveats though it comes with less familiar anatomy less working space but again the quicker access to to posterior tumors and to the base i think it makes it advantageous for those select cases now this is a very common uh question and topic of discussion among kidney cancer surgeons how much of a margin is enough when should you do a standard wide excision partial refrectomy versus tumor and nucleation and um and so the way i think about it is when when we really need to preserve renal parenchyma when that's paramount then tumor and nucleation can be beneficial so you can see at the bottom patients with certain types of familial rcc syndrome so not not sdh not hlrcc we heard those are bad actors but for for the other ones for von hippel lindell for birdhog dubai for hereditary papillary renal cancer these are good candidates for tumor and nucleation they have robust pseudocapsules and they're at risk for multiple tumors throughout life so preserving parenchyma is paramount for patients with certain types of multifocal disease that don't have a genetic basis and for patients with severe ckd all those patients can benefit from tumor nucleation for the uh the most common scenario though the patient with a three centimeter lower pole renal mass uh who's in their 60s and does not have a hereditary predisposition it has normal kidney function a nucleation is not necessary and in fact you might be better off taking a margin of normal renal parenchyma in that case to uh to ensure that you have good oncologic results but the benefits of tumor nucleation besides preserving the parenchyma for certain complex masses it's helpful to be able to see the edge of the tumor as you're going around and particularly to avoid entry into the collecting system or for hilar tumors to avoid um inadvertent entry into the renal artery or vein and if you're doing if you're doing an off clamp approach which we'll talk about in the next slide you know even if you a nucleate you're going to have much less blood loss than if you take even a small amount of renal parenchyma so to me tumor nucleation and off clamp sort of go together in my mind and so off clamp when do we do this well a common scenario that that we see at the nci are a patient that presents with multiple tumors and we can't we can't clamp the kidney long enough to safely get five tumors out without a detriment to the uh to the uh renal remnants so there are certain cases where we are obligated to at least tackle some of those off clamp for the patient with a solitary kidney uh i think less ischemia is better there particularly if if you think there's gonna be prolonged ischemia there are many times where you can start off clamp and only clamp for it for the deepest portion of the tumor to uh to really make sure that your interval is not too long for patients with previous kidney surgery or the renal hyalumos card sometimes you can't adequately clamp the renal vessels and there are times that could be a consideration and particularly germaine for patients with hereditary syndromes and planning for future surgeries if we're dealing with a very exophytic tumor where it's not going to bleed this time maybe we don't fully dissect the hilum because we know that in five to ten years we will have recurrent tumors and they may be in a location that's not admittable to an off clamp approach so many people in their training have only done wide excision partial nephrectomy so what does it look like to do a tumor nucleation let's see if this video will yeah so what we're doing in tumor nucleation the highland is not clamped here we're really brushing every millimeter of parenchyma often until we see the very shiny surface of the renal tumor pseudo capsule there's some bleeding that can be that can be addressed with manual compression with a sucker but you can usually avoid arterial bleeding and you can see that if you're in the in the perfect nucleation plane where you don't have the strings the fibers of renal parenchyma that hemostasis can be can be it's not a challenge and so the next step here would be to to do your renewably so let's come back to this this case so we decided to tackle the left side first and you can see this is a large tumor and it does above the the renal sinus but um i thought that there was a higher chance of saving the kidney here than for for the other side so thinking about decision making we decided to tackle this robotically because it's large even though it's posterior because of the large size i did not think we would have adequate room via a an rp approach so we did transparentenil i did a wide excision because it's larger and i was worried about oncologic efficacy and because i'm doing um a wide excision because it's deep i did elect to clamp the hilum so what that looks like we just saw a tumor nucleation for wide excision you really are starting not on the pseudo capsule but just a little bit off and the the difference here you can see the sort of the fibers of renal parenchyma rather than that smooth capsule and that's how you know that you're in the wide excision plane rather than the tumor a nucleation plane we're clamped so so blood loss uh is not really a consideration here we have a nice uh visible margin uh throughout and um because this was larger the skimming time was about 29 minutes we lost 350 cc's and the pathology was consistent with an 8.5 centimeter chromophobe rcc negative margins and he had a good kidney function at discharge now interesting the other side was biopsied as clear cell this was a chromophobe you know there's only about an 80 percent concordance rate when patients have sporadic patients present with multiple tumors so we we do see multiple histologies and we have seen patients who have benign histologies maybe they have an aquacytoma and a clear cell on the other side so something to always keep in mind you can't assume that what is on one side is necessarily what is on the other so six weeks later it was time to tackle the right side and so this is a completely endophytic tumor uh you can see there's no bulge at the renal capsule it's completely independent covered by about almost a centimeter of normal renal parenchyma we decided to tackle this robotically again transperitoneal wide excision and declamp when we uh when we uh went in though we saw the tumor on the ultrasound you can see in the middle of the screen and it is intimate with the renal sinus and the hilar vessels as we circle there intimate with the vasculature so you can do a partial nephrectomy here but my concern with a clear cell versus the chromophobia on the other side a clear cell here in this location can often be infiltrative into this renal sinus fat so we made the decision actually to convert this to a radical nephrectomy uh and i'm glad we did this was ended up being a furman grade 3 clear cell with extension into the renal sinus fat so a pathologic t3a i'm happy to report the patient's doing well uh did not need renal replacement his final gfr was around 40 so so he does have ckd um but he is not at risk for uh for dialysis and he's been tumor free for the last 18 months so case number two this is a a woman in her early 40s who contracted copic 19 had had some symptoms so had chest imaging and on that chest imaging was found to have a renal mass or renal masses she was otherwise healthy with no core medicine comorbidities interestingly she did have a family history of spontaneous pneumothorax but no history of geo-malignancies so this was the cross-sectional imaging that the patient had you can see multiple large renal masses in both kidneys large summer deep some are abutting the sinus fat so when we see a patient like this how do you proceed with workup and there are a lot of options here we could think about biopsy this is a patient who who is young so maybe there are considerations for for hereditary kidney cancer causes as well and so this is work that was done by brian chuck when he was at the nci looking at defining early onset kidney cancer and the crux of this paper was comparing the seer database of patients with sporadic kidney cancer to those with a diagnosis of hereditary kidney cancer and was found that the sort of the cut off that best predicted hereditary and had the sort of most false uh had the least uh false positives for sporadic was at an age of 46 or less and work presented this meeting by uh by one of our fellows alexia run paper door he found that for patients with enrichment features for on um for hereditary kidney cancers so for bilateral multifocal for early onset or for familial renal cell cancer that them the more of those features you have the more likely you are to have a positive germline test and so for this patient we did do genetic testing this patient had bert hog dubai a alteration in the follicular gene we decided to use a sestamibi scan here to uh to further characterize the sestamibi as a mitochondrial imaging agent and for tumors that are mitochondrial rich including oncocytoma or hybrid tumors seen in bhd those are will light up these all lit up consistent with hybrid tumors so because this patient had hybrid tumors which are thought to be of low genetic low biologic potential in terms of metastasis and recurrence we were able to offer this patient a robotic transparent needle a nucleation with a mixture of unclamp and off clamp techniques so this patient went uh staged bilateral partial mafrectomies uh six tumors were removed on the left side uh the largest was eight centimeters all were hybrid tumors and five tumors were removed on the right largest were eight all were hybrid and the patient had a post-operative gfr uh of 81 and what what made this really possible was using a nucleation whether rather than wide excision you can see the the post-operative scans here so this patient is now in ed about about 12 months after surgery now so in terms of uh partial nephrectomy the decision on to perform really you're weighing the oncologic risk versus competing risks of surgery for any individual patient it requires the input of patient tumor and surgeon factors what are you comfortable with what is the patient comfortable with in terms of the risk of surgery versus recurrence versus surgical complications but being facile really with each of these four axes gives you a lot of options you know two to the four or sixteen different surgical options uh for partial nephrectomy and so i have just a couple minutes left but i do want to briefly touch on how we think about cytoreductive nephrectomy now this is a topic that's garnered a lot of attention for many years but especially in the last uh last three years with the uh with the publication of the carmina and and surtime studies so uh just very briefly this is a 47 year old patient who presented with 10 pounds of weight loss night sweats and anemia imaging showed a left renal mass and multiple sub-centimeter pulmonary nodules she had hemoglobin of 8.3 all other labs were negative so you know you plug this into the calculator to the mskcc or the imdc calculator this was an intermediate imbc intermediate patient and so we can see the imaging of the renal mass on the the video is not loading here large renal mass and you can see the um on the chest imaging we have several pulmonary nodules well uh round well circumscribed pulmonary nodules the largest is about nine millimeters a total of three pulmonary nodules so what are the treatment options for for a patient like this is this a a patient a good candidate for upfront cytoreductive nephrectomy would a biopsy be helpful here what about upfront systemic therapy and i'm sure that there could there could be reasonable disagreement on the best way to proceed for this patient maybe maybe show of hands in the audience you here would would think about upfront cytoreductive refectomy for this patient okay what about upfront systemic therapy okay yeah about about 50 50. so in in this case uh the patient elected upfront cytoreductive nephrectomy uh and the reason we felt good about this option was this patient had a large disease burden within the kidney um had pretty limited disease burden outside the kidney you know really such that we would not necessarily this patient would not necessarily need to start systemic therapy right away and the the eau guidelines suggest that if a patient has minimal disease outside the kidneys such that they would not require immediate therapy maybe that's that that could be an appropriate patient for cytoreductive nephrectomy uh what was interesting is her anemia resolved this was a paraneoplastic anemia resolved completely her night sweats fatigue these symptoms all resolved uh she did start epinevo uh two months after surgery and she's alive with stable disease she still has these pulmonary nodules that are really the same size as they were then they were eventually biopsied they were confirmed anesthetic but she's doing well this patient also had a lymph node dissection because we saw what we thought was an enlarged node at the time of surgery it ended up being benign but to you know it's a common question what do we do when do we do lymph node dissections and the the answer that the literature currently supports this really comes from mayo which was a center that did a lot of lymph node dissections is that it makes sense for a patient with clinically enlarged nodes for most patients without clinically enlarged nodes there's probably not a role for upfront lymphadenectomy now there are some subtleties we there are some um diseases that we manage like hlrcc where maybe lymph node dissection up front does make sense but for the for the average patient who presents with a large renal mass and no negative clinically no negative disease those patients probably do not need a lymph node dissection in the interest of time i will just show to compare that first case this was a patient that presented around the same time with a large renal mass and what we thought was limited disease on the outside scan when we staged them with an mri you can see too numerous to count lesions within the liver so this patient presented with hepatic osseous and and soft tissue disease as well as enlarged lymph nodes who would do a a cyto-reductive refrectomy for this patient yeah this patient multiple sites of disease a lot of extra renal disease burden so this patient actually went on to have systemic therapy she was imdc poor risks with three three risk factors and she's done well now for about 18 months on systemic therapy although she has has progressed through a couple of lines so in the interest of time um these there's some data that's in the handout that's available through the swap card app i encourage you to look through the the history of sort of why we've done cyto interactive cyto reductive nephrectomy in the past maybe some of the challenges that the carmena data have um have added to that and to the to the surtime studies as well but i will say that in the future there will probably be more of a role for patients to receive upfront systemic therapy uh with with consolidated nephrectomy overall i think surgery will still play a big role in the space but i think that will change as we get better therapies so thank you very much for your attention and happy to answer questions at the end and we'll move along thanks dr ball i'm very happy to introduce dr david mcdermott he's from the beth israel um deaconess harvard cancer center we're thrilled to have him international expert in this david thank you for coming i'd love to hear the exciting new work you've got okay well i always appreciate uh getting invited to aua um any surgical meeting actually i'm going back to i'll tell this story as they work to get my slides up i guess going back to medical school i'm sort of a wannabe surgeon you know couldn't couldn't quite hack it but i always looked up to a lot of my surgical colleagues in my class they were always sort of the cool kids in class and a lot of my chief residents were very impressive people you know the other reason i like talking to surgeons is you know you guys say kind of cool things like the chance to cut is the chance to cure you know that was one of the big cliches back in medical school which always seemed interesting to me and it's that point about surgical endpoints that you understand that actually many of my medical oncology colleagues don't focus on and immunotherapy at least in some cases you know i focus on developing solid tumor immunotherapy can deliver and and that's what we'll talk about today we'll talk a little bit about immune therapy for kidney cancer and its role i hope and then how it fits into your surgical management of your patients it's where are we with this yes sir you want me over there okay we're gonna hurt we're just gonna get his slides up dr mcdermott's gonna go over and look while he's doing that uh i want to ask a couple questions of uh dr ball dr paul i wasn't really clear on the business about when to do lymphadenectomies or not could you give me that again just sort of i've seen a patient uh when do i do lymphatic nectar absolutely they sound straightforward yes so um you know it really boils down to is there are there enlarged nodes on imaging so a patient who has enlarged nodes uh who is otherwise is going to surgery i think it makes sense for that patient to to have a lymphadenectomy and the data would support that not all patients with enlarged nodes will have metastatic diseases in those nodes but many will conversely for the patient with clinically node negative maybe they're high risk it's a large tumor or there's a renal vein thrombus the data doesn't support to do a routine lymphadenectomy in those patients granted sometimes there are game time decisions you see something interop that you don't see on imaging but to do that routinely would would not be the the answer that's supported by the literature in 2022. all right let me upgrade so okay that helps a lot so let me ask another question i'm a little i'm a little confused about this so we talked about genetics and genes and all these different things about kidney cancer that's great it helps us think and all this that and the other however i'm out there i'm a urologic surgeon patient comes to me with a uh i don't know let's say a three centimeter renal mass um when do i take it out when do i not when do i nucleate when do i go wide also uh you know i don't know i hear about these papillary things maybe they can be worse okay here's some guy comes he's got no family history got nothing that i know he doesn't know his family i don't know anything what do we do when do you biopsy or not or can i go on your radiologist on the imaging i mean you know we've all seen some things that didn't turn out so well some did a partial at a positive margin you know what do you how do we think about this the nice thing about about practicing today is we have more tools than we've ever had to to attempt to risk stratified patients i think that um you know biopsy is increasingly utilized and you know some people argue that you don't need to do biopsy because it doesn't change management and it doesn't always but there are many times it does for for a mask that maybe is located in a difficult location where radical nephrectomies on the table i think it makes a lot of sense to do biopsy um you could uh you might maybe the patient has an oncosatoma and and you they don't need a radical neuropectomy for a three centimeter oncotoma so i think that it's in it's imperative to discuss the option of biopsy with with every patient and you know counsel them accordingly about uh about the risks we have uh features we can glean from imaging from both conventional imaging with contrast enhanced mri or ct we also have newer nuclear imaging techniques like sestamility scans that can differentiate oncocytomas and oncositic tumors from from clear cells and others so for the but for the patient where we maybe we don't have some of these more uh more novel tools they have a three centimeter tumor that looks amenable to partial nephrectomy does that patient need a nucleation i i probably would not because i don't know what we're dealing with maybe it's maybe it's an aggressive clear cell um probably not most of the time it won't be but sometimes it will be and and you will regret that if you if you take a minimum margin okay let me ask dr senator vazquez and a question next time you heard dr bald appear talking you're of course a medical oncologist and you know work with we all work together but but let me ask you this dr ball was talking about side erect nephrectomies for people with advanced disease okay now hear our audience here we are i'm a urologist i'm in the real world i'm seeing a patient come smooth advanced disease i biopsy them and uh you know it's clear cell but i biopsy them it's papillary you know there's some funny papillaries out there and this that and the other uh how does that make a difference in it to where of course this you know it's a joint it's a joint thinking between the urologic surgeon and the medical oncologist i realize that but where do you come in on this i mean as far as as far i know you give a lot of thought to this as far as active surveillance uh uh cytoreduction nephrectomies and also are there any people with metastatic disease maybe kidney in place even that you would say let's don't do either let's just watch it you know what what do you think i know this is a little more complicated than i thought it was what what's your thinking on that well you know what maybe we'll hold that are you ready let's hear it so maybe we should let him talk oh here we go dr mcdermott's ready to go so i'll come back to questions i want to hear your thoughts about that and dr mcdermott thanks a lot all right thank you sorry about that um so back to what surgical endpoints i mentioned they're they're more interesting i think than medical endpoints let's talk about how those play a role with immune therapy and solid tumors here are my disclosures i mentioned also that i look up to several surgeons this is one of them this is a picture in the top left of steve rosenberg one of dr lenhan's colleagues at the national cancer institute surgery branch he and others at the group essentially developed the field of solid tumor immunotherapy initially with cytokine therapy with high dose il2 you're looking at actually at an x-ray here of a patient with metastatic melanoma in those days this is pre-ct scan you can see a dramatic response with high-dose il2 in those patients and this is a response duration curve that my colleague dr mike atkins has also shown on this picture developed for patients receiving hydrocele 2 and kidney cancer and you see patients with responses those responses going out 10 years well after surgery well after therapy has stopped those patients are living in remission of their disease so essentially high-dose il-2 proved an important principle that remission or cure was possible with solid tumor immunotherapy but unfortunately because these responses were relatively uncommon and the toxicity was significant and you were giving the medical oncologists would need to give this therapy um who are less brave than surgeons at the nci this this approach did not really reach that many patients with either melanoma or kidney cancer not until some discoveries that actually led to a nobel prize in medicine a few years back that went to dr hanzo who's shown on this slide not until we started to understand how tumors can actually shut off an immune response and maybe how we could block the interaction between tumors shutting it off on immune response and getting a tumor immune system to kill a tumor not until these discoveries of dr gordon freeman and others did we actually make major progress in the field of solid tumor immunotherapy so-called dr freeman helped us understand how pdl-1 expression on tumors could be blocked and could lead to tumor regressions did we start really making major progress in this disease in kidney cancer sort of the paper that led to the approval of pd-1 blockade with nivolumab um was this one here in new england journal of medicine dr motzer led this work in patients who had failed prior vegf therapy nivolumab was superior to mtor blockade leading to its approval about seven years ago but for most patients we see a little background science here most of the patients we see in the clinic with tumors actually present in what we call immune escape as you can see on this slide sort of the three e's of immune editing when you give them pd-1 blockade you can reset that balance between the immune system and the tumor actually gaining more control over the immune over the tumor leading to sort of an equilibrium but for most patients in mo in most cases not just in kidney cancer but for example in bladder cancer we're not seeing the complete responses that we saw with hydrocele ii we're seeing sort of an equilibrium that's usually temporary for most patients you know they we gain control but eventually the tumor figures out how to escape we're not eliminating uh the tumor so how might we do better as far as eliminating tumor well the obvious next step for for many in the field was let's think about combinations let's try to enhance the anti-tumor immune response by adding other agents that have been shown pre-clinically to enhance the immune response to the tumor there was certainly some evidence that veget blockade did that in mouse models either by improving the infiltration of t cells into the tumor or enhancing for example the impact of dendritic cells also ctla4 blockade and its role in priming and activation of the immune system was thought to play a role in so logical next steps once we had pd-1 as our base was let's add to it in different ways and that's what folks did and essentially the some of the initial trials were essentially fusing the old first line which was vegf blockade with the new second line which was pd-1 blockade and quite a few trials were launched with these combinations the first one to show significant impact was this one here pembrolizumab and exit nib was shown to be superior to synitnib in the frontline treatment of patients with metastatic kidney cancer you know um you know essentially changing the changing the paradigm for how we treat many of these patients subsequently that was built upon by the combination of pd-1 and ctla-4 once again dr motzer leading this also showing superiority to synitniv so leading to also pd-1 and ctla-4 becoming a standard approach for untreated kidney cancer patients with metastatic disease we've essentially seen a series of of positive pivotal trials in the front line setting most of which have the same design most of which are vegf plus pd1 um nivolab and ctla4 have been the only outlier from a mechanistic point of view and we spend a lot of time at medical meetings trying to decide which regimen of these options should be favored if you look at sort of the clinical take-homes of these different approaches when you're trying to decide what to offer your patients there are pluses and minuses with each approach as shown on this slide with pd-1 and vegf we see improved survival which is great but we also see higher response rates and a small number of patients who progression of disease is their best response and longer times of progression-free survival with ctla-4 we see overall survival improvements and we see what we'll focus a little bit about we also see durable responses and the potential to stop treatment and having the benefit be maintained and you know we could spend some time debating this question honestly honestly i don't know that you care all that much and to me it's kind of a waste of time because it would require us to do cross-trial comparisons which we all know are flawed these trials have unequal follow-up durations so it's hard to make comparisons and also when we're talking in front of medical oncologists there's no agreement on what i would call the hierarchy of endpoints like what endpoints for these trials are most important for you or most important for your patients we'll talk a little bit about that getting back to my surgical days you know early endpoints i would describe as endpoints that happen you know in the first two years of treatment these are favored by industry for obvious reasons to try to get answers to their questions early and they're also used by the fda for many of our approvals they're certainly important for symptomatic patients so if you have a patient with metastatic kidney cancer who's symptomatic you want a response so an agent would like vegf and pd1 that will offer you a chance at a major response early could be preferred but late endpoints are often important for patients and i would describe late endpoints as those that develop after two years of treatment these are also favored by many of you in in surgery and by our colleagues in stem cell transplant where you see a patient with a tumor you take the tumor out and you walk away and the patient and you only congratulate yourself if the tumor is all gone you know no one no one pats themselves on the back for a partial resection of a tumor and because it allows the patient to live in remission off treatment and nodding not needing a referral to medical oncology and the the endpoints that measure a durable response are things like duration of response landmark progression-free survival and long-term overall survival but i'd like to add a third class of endpoints into this discussion which are the so-called durable endpoints and like surgery they develop after treatment stops and many of my medical oncology colleagues are actually very hesitant to stop treatment even when it's working but it's also often favored by patients because as soon as you come off treatment you come off the side effects of treatment and we're developing a sort of a comprehensive measurement of the benefits of immune therapy we call treatment-free survival which i'll talk about in a second which tries to give us a sense of both the pluses and the minuses of immune therapy for a population so when we when we're comparing these studies what do we see with more follow-up well interestingly when you look at overall survival the overall survival numbers for pd-1 vegf were tremendous initially but with more follow-up the hazard ratio for overall survival is going up in many of these studies and also if you look at the favorable risk group which is the group where vegf levels are the highest in general hazard ratios are going up even more dramatically in that group which is not what you would expect i think if blocking vegf was leading to an improved immune response to the tumor in in contrast when you look at pd-1 ctla-4 over time while the hazard ratio for overall survival was not as impressive early on when you look at follow-up those hazard ratios are staying stable and they're actually improving for favorable risk patients moving to progression-free survival comparing the two approaches you see a plateau in the progression-free survival curve for pd-1 and ctla-4 about a third of patients are alive progression-free on that trial at five years many of those patients are in remission of their disease whereas with pd-1 vegf those curves are sagging now they may develop a plateau over time but they haven't yet and this may be true for a number of these different combinations so when deciding which option of pd1 based combination therapy is best for your patients it depends on what you're trying to achieve an early improvement then pd-1 vegf makes sense a durable improvement so far the data with pd-1c tila 4 are encouraging but we need more follow-up and that and then we'll talk a little bit at the end of this talk about the durable outcomes that we see post-treatment so-called treatment-free survival you know but comparing these regimens you know we could spend a lot of time doing that but i think the actual more important question is if we can create remissions of metastatic kidney cancer if you actually believe that's possible if your answer that question is yes then i think as a field what we need to do is work to make that more common as our primary goal not the only goal but as our primary goal so you know my colleagues as dr lenehan mentioned at dfhec are focused a lot on that this is the group who leads that effort up in boston and i'm going to talk a lot about their work one of the things we focus on to try to make cures more common in kidney cancer is to continue to rationally apply this approach through developing biomarkers that are predictive of response because ultimately immune therapy should not be provided broadly to all of our patients they're just some patients particularly those who do not have a pre-existing immune response to their tumor that are never going to benefit from immune therapy so how do we identify those patients well in kidney cancer it is not easy in part because of what we see in many of our patients this so-called intra-tumor heterogeneity that the the group from england the tracer rx group has told us about for over a decade this makes biomarker development almost impossible in kidney cancer but doesn't mean we shouldn't pursue it and there are many different groups that have pursued many different tissue based biomarkers for outcome the best one at least at the moment right now and this goes back to your original questions is probably sarcomatoid histology where if you look at patients with some aspect of sarcomatoid astrology in their tumor and their long-term outcomes their their plateaus on their survival curves are impressive even better than all comers so of all of these probably progression-free survival is at least the moment the best predictor of outcome if you see a patient like that they should almost certainly get pd-1 based blockade therapy initially we're taking this even further this is a recent publication in cancer cell trying to subset individual kidney tumors based on molecular signatures these are rna signatures in the tumor and we're we're making some progress but it's not yet ready for a time as sort of a companion diagnostic but with this work it looks like tumors not surprisingly who have a rna signature that's full of t-effector cells signatures they're more likely to respond to immune therapy those tumors with vegf signatures more likely to respond to vegf alone and then there's some patients who are not going to benefit from either approach and we shouldn't be offering them immune therapy in my opinion we're asked to provide a case this is one of my patients a 65 year old man who the past medical history of obesity and diabetes had a large right renal mass otherwise you know normal blood tests he underwent a nephrectomy for this tumor that you see here in the the right renal mass and then the question was the patient was referred to us for consultation the question is what's the most appropriate next step for this patient and you see your choices um and there are there's potentially more than one right choice to this but number the answer number four is going to become an increasingly correct answer potentially for these patients um based on this trial here that was published in the middle of last year in the new england journal of medicine this looks at bringing immune therapy earlier into the paradigm which is where we're starting to see some encouraging results in multiple tumor types this is bringing it mainly into stage three patients comparing it to placebo dr shueri led this study and here is this is the so-called keynote 564 study where patients were randomized to receive pembrolizumab for up to a year and here are the results disease-free survival improved for patients getting pd-1 blockade with the hazard ratio of 0.68 this was an encouraging result and led to the drug's approval and if you look at that improvement though based on a different pre treatment characteristics it's a lot of the benefit is being driven by at least at the moment by patients who presented with metastatic disease and had their disease resected and then they went on the study so time will tell if this is an approach that we should be broadly applying to all of our patients or just to patients with more aggressive cancers or more aggressive presentations and if one of the interesting things at least initially is there seems to be at least a small survival signal obviously there are not many events driving this but this will be important in determining who we use this for us does this survival signal last with time it may or may not in in you know what are we learning from other tumor types as it relates to adjuvant therapy while i also treat melanoma and we steal a lot of great ideas from them because it's been a pro therapeutic proving ground for a lot of solid tumor immunotherapy well if you look at immunotherapy application in melanoma it's approved right now for all stage three patients in the us based on this data and other data but essentially it's not being used for 3a patients at most academic centers in large part because there's probably not a great balance between the toxicity that you see with the agent and the true risk of patients recurring so this is sort of a post-approval modification that many of us have used just to follow 3a patients which are frankly the most common patients we see in academic centers and this could happen also in kidney cancer meaning a blanket approval early that gets modified hopefully by tissue-based biomarkers in the future and you know just sort of getting to the end of my talk i want to talk a little bit about novel endpoints that might appeal to surgical colleagues this is the so-called treatment-free survival comprehensive method that i mentioned earlier where we're looking at survival states over the course of all of the patients on a study and and had they do you know in purple when they were on protocol therapy in blue when they were on the study but off therapy um in gray they're on the subsequent treatment and obviously black is uh death um we actually compared outcomes you know comparing treatment-free survival and survival states with pd-1 versus vegf and not only was overall survival as i mentioned greater with immune therapy than vegf blockade but treatment-free survival was twice as long so you are more likely to be alive and twice as likely to be alive off treatment now that's at risk you know so obviously immune therapy brings greater potential durable risk and we're also measuring durable toxicity as part of this is part of this method but it's a trade-off that's at least worth a discussion with patients in our opinion what else are we doing what are we learning from actual patient tumors besides predicting prediction criteria that might improve our immune response to the tumor we're actually trying to interrogate the tumor micro environment to develop new therapies i don't have too much time to talk about this but things like neo-antigen-based vaccines novel immune checkpoints car t cells are being developed in kidney cancer until therapy is also being developed in kidney cancer some of my colleagues at harvard are trying to use information from the tumor to say you know what are the best targets you know we should be going after this is work by david braun who's now at yale and kathy wu who's up at dana farber you know using single cell sequencing to identify exhaustion targets one of the targets they found is present in a lot of the immune cells in kidney tumors is lag three which is another immune checkpoint pathway recently in melanoma once again stealing from melanoma um pd1 plus lag three has been shown to be superior than pd-1 alone and has gotten fda approval and combination of melanoma we're trying to use the data that kathy and david have generated to hopefully convince companies to develop this combination in kidney cancer trying to do it in a rational way it's a lot going on back here the also we're trying to develop even novel checkpoints that haven't been identified by industry once again going back to gordon freeman here and my colleagues at uh beth israel kathleen mahoney and rupaul bot identifying a new pathway they think could be important the so-called hhla2 tier 3 dl3 pathway this is a pathway that's normally stimulatory to t cells but they've actually found a a receptor that's actually inhibitory to t cells that can be drugged and this pathway is present expressed on many different tumors so they're hoping to drug this pathway in similar ways that we drug ctla for in hopes of enhancing an immune response to a tumor so once again taking human samples and trying to identify new targets for immune therapy i mentioned a car t is also in early development till therapy where you this goes back to the early days at the nci and i'll finish up here where you actually take the patient's tumor you take it out surgically you um prepare the patient's immune system by suppressing it with chemotherapy and you give back these energized tumor infiltrating lymphocytes in the context of hydrocyal too so it's sort of the kitchen sink of immune therapy this has shown some impressive results in melanoma and lung cancer and cervical cancer and we're hoping to bring it into kidney cancer at least in the clinical trial space it's possible this will get fda approved for melanoma sometime in the next year there are several companies working on this so i hope i've been able to convince you that my colleagues are doing some good work bringing immune therapy closer to the front to the earlier in the disease with adjuvant pd1 blockade importantly focusing on endpoints that are surgical in many ways but focus on patients and their um their desire to live in remission of their disease like treatment-free survival and also you know folks are doing some interesting scientific work marston mentioned this earlier and ron will talk about this in his next talk my colleague bill uh kailyn won the nobel prize for some of his work in targeted therapy for kidney cancer you know looking at targeting that they have to alpha transcription factor and you'll hear more about that in the next talk uh assuming it's happening um and and hopefully we'll get to the point by throwing all of this together um the standard therapy when we get together maybe ten years from now is we're going to rationally apply immune therapy based on the profiling of the tumor microenvironment and increasingly second line therapy will not be necessary because we'll have more patients uh living in remission um you know and not on therapy so these are my uh colleagues who contributed to all this work obviously my nci folks colleagues who i cherish who worked you know hard on the vhl hiff story that will be in the story in the next talk but we're excited to be here and i'm glad to take any questions thank you thank you dr mcdermott i mean it's just amazing to me uh to think about where we are with the science how much it's going to impact how we as urologic surgeons manage patients with you and you know it's funny you mentioned till therapy i remember the first you're not going to believe this but the first teal therapy given to a human was grown in my laboratory by arie beldagrun if you can believe that way back when he was a fellow and retreated a pain he treated a patient uh one evening uh with that and patient actually had a very nice response and uh anyway while we're getting a doctor cervezan slides sorry about the it's just we're getting it all squared away let me ask you a question though i'm kind of interested to know a couple things one um what would you and i love your emphasis on cures you know that's what we need to be focusing on now what would you get i know you did a lot of thinking about this and presented some incredibly exciting data we've made so much progress let me ask you the following what would you think with all your years of experience as far as what might be the final solution what might lead to cures okay why don't you go ahead and answer that in induction advantage well i i think at the moment i mean combination of drugs targeted plus immuno what do you think well um i think we're already curing patients with metastatic disease we've been doing it for 30 years with immune therapies like hydrocele to we do it with combination pd-1 blockade now but we have to be willing to see that outcome we have to be willing to stop the treatment in our best responding patients which a lot of colleagues in industry is certainly not they're not willing to explore stopping drugs so i think that those cures are out certainly those remissions are out there um but it's not all going to be an immune therapy story there are patients with whose tumors are going to be completely resistant to immune therapy and then we need to be developing novel targets for those patients we're going to hear some of that in this talk now i don't think targeted therapy is dead for kidney cancer but we need to be more like our lung cancer colleagues where we identify the pathway that's driving the tumor and we provide the drug based on that instead of what we're doing now it's sort of a broad application of all the drugs that we have i think that's going to slow us down and that's where the unfortunately that's where the field is going is the next step i didn't get into this but we're starting to go into triplets for just all all comers and i honestly think that's going to slow us down okay personally right happy to have dr rahm servasin he's going to talk about novel treatments for kidney cancer genes to therapy dr chanvassen thank you dr linhan and it's a pleasure to be here this uh this morning to be wrapping up this session and i think dr mcdermott's comments you know provide a great segue into the topics i'm going to be covering today i'm a medical oncologist by trade but i've worked with urologists and neurologic oncologists for the last 17 to 20 years and i can tell you confidently that over this period i've started thinking a little bit more like urologists and i dare say that my urology colleagues have started thinking a little bit more like me i think it's good for the field that you know multiple lines of thought come together because i think that i think is the way to true development one of the common jokes uh within our group is that i recommend more surgical procedures than the surgeons do it's easy for me to do because i'm not actually doing the procedures they are but hopefully i'll show you over the next 20 minutes or so how working together as a group urologist medical oncologist basic scientists has really helped us advance you know some really novel ideas uh into the clinic and we'll see at the end of the talk what you think dr linehan talked to you about how diverse kidney cancer is and just because we call these these various entities kidney cancer doesn't mean they're all identical a variety of different genes uh driving a variety of different histologic subtypes of cancer all of which seem to occur in the kidney with all the knowledge we have about how these different forms of kidney cancer arise and occur it would be a shame if we didn't exploit that knowledge really to design targeted therapeutic strategies that were individualized for these uh distinct subtypes and that's what we have tried to do uh in our group uh over the last 15 years or so i'm going to be spending most of my time here today talking about specific forms of clear cell kidney cancer and papillary kidney cancer the two most common forms of rcc that we encounter in clinical practice as you know the basis for targeted therapy approaches in patients with clear cell kidney cancer has really been understanding the vhl pathways so most of the early treatment options that we've had for treating patients with advanced clear cell kidney cancer came from an understanding of how loss of the vhl gene leads to kidney cancer formation and while we were initially unable to target some of the key downstream events uh that followed vhlos we were able to successfully target several downstream consequences of these of these events uh and successfully for quite some time uh with the advent of immune checkpoint inhibitors as dr mcdermott mentioned a few minutes ago uh the treatment in the last four to five years of clears the kidney cancer has altered dramatically we use combinations of checkpoint inhibitors the volume up plus equilibrium as dr dr mcnamara mentioned in the treatment of some patients with advanced clearance of kidney cancer but also used widely combinations of immune checkpoint inhibitors and the very same uh you know targets that agents that target consequences of vhl and activation accident for instance gabazantner was another agent that's been combined successfully with immune checkpoint inhibitors lenvatinib is a third agent that is commonly in use in combination with immune checkpoint inhibitors in the management of patients with advanced care cell kidney cancer while understanding the vhl pathways really helped us more effectively treat patients with advanced sporadic forms of clerical kidney cancer we asked how we can utilize that information to treat patients with with vhl disease a condition that urologists are a lot more familiar with than medical oncologists vhl disease needs no introduction to most of you as you know it's a multi-system cancer disorder uh predisposing patients to develop tumors and multiple organ systems including bilateral multifocal clear cell rcc uh the story begins in the early eighties when marsden linehan berg zabar and others at the nci decided that they needed to try and understand why patients with vhl get these cancers and so they collected families with with this with the syndrome and very carefully studied them to identify a gene called the vhl gene located on chromosome 3 that seemed to be altered in the germline of these affected patients we now know that the very same gene is altered by somatic mutations in patients with sporadic forms of clear cell kidney cancer it took another 15 years or so to fully understand how loss of the vhl gene leads to kidney cancer a lot of work done both in the enhanced lab labs of these gentlemen who won the nobel prize for medicine and physiology in 2009 uh 19 and a number of other labs uh who i can't really mention in this in the short talk uh really allowed us to understand that hypoxia or pseudohypoxia is a key element mediating vhl dependent kidney cancer and that is what led to all the efforts i've talked about so far that effectively target alterations in this pathway so why should we even be looking at systemic therapy for patients with vhl how do we manage patients with vhl you heard a little bit about this from dr linehan and dr ball the goals treating patients with vhl are twofold one is to minimize the risk of metastasis and this is applicable to those tumors which have metastatic potential kidney cancer pancreatic neuroendocrine tumors fear chromosatoma but we also treat patients with tumors with a view to controlling local symptoms or systemic complications once metastatic we don't really know how to treat these patients and we treat them the way we would sporadic counterparts of the respective histologists histologic subtypes while these treatments have been very effective and we've managed to treat patients with vhl quite effectively with surgical techniques any of you who's treated vhl knows that the surgical approaches are associated with significant comorbidities because you often have repeat surgeries multiple times during a patient's lifetime with all the you know mobilities those procedures incur so there's a real need to develop therapies that may give patients a break from from surgery or at least minimize the number of surgeries they may have to go through in their lifetime and that is why we and others became interested in developing systemic therapies for these these patients an ideal systemic therapy would be able to achieve a lot of the things that surgery does so prevent tumor growth prevent the potentially onset of new tumors with surgery can't necessarily do minimize the risk of metastasis but also provide a quality of life that's acceptable and allow these patients to go about their business as normally as possible initial attempts to treat these patients with systemic therapy utilized wedge of targeted agents several trials are listed here and i'll quickly summarize what we saw with those trials using these two drugs and studies as an example we saw some activity uh particularly in renal tumors associated with vhl when we treated patients with uh with vendetta nippers open up synthetic other agents in this category we didn't see a whole lot of activity in non-renal tumors but what we did see a lot of was side effects many of these patients were unwilling to accept the side effects that patients with metastatic kidney cancer who had you know very limited alternatives were willing to accept so as a result most patients went on study and off study fairly quickly and so this was not really a long-term viable option of course what we'd really like to do was target f2 which we know is a very key driver of uh kidney cancer and in the vhl deficient setting this is a very difficult target to drug and it took you know a couple of decades of efforts to really nail down a method to try and target these uh the target hif with small molecules and the result was a class of agents small molecules that was able to effectively disrupt uh the formation of a heterodimer of hef2 and hefty alpha and hif one beta heterodymerization that's essential for function of of this transcription factor the first agent in this category was called pt 2385 and we at the nci did a very small proof of concept study looking at this agent in patients with vhl associated renal tumors very early on in the study it became very clear that this drug was different the tolerability profile is much better than what we saw with wedge of targeted agents and we also saw very ready regression of tumors in the kidney in neuroendocrine pancreatic neuroendocrine tumors cns imaging blastomas and even eye angiomas so we were very very excited but there were some pharmacokinetic limitations to this particular drug which fortunately uh the scientists at peloton the company that that developed these drugs was able to overcome by developing a second generation heft to alpha inhibitor called belzodifan also known by various other names listed here so we then took this drug in collaboration with a number of other vhl experts around the world and with peloton and merck and designed a multi-center global study to evaluate the efficacy of this drug in patients with vhl associated rcc the primary endpoint of the study was overall response rate in kidney tumors but we also looked very carefully at toxicity of this agent as well as responses in non-renal lesions we enrolled a total of 61 patients the trial accrued fairly rapidly which was surprising to us but also gratifying because this is a relatively rare condition the the patient demographics were very typical of what you would expect for this this group of patients but in addition to pa kidney cancer all patients had at least one pancreatic lesion including 22 patients who had a pancreatic neuroendocrine tumor 50 patients had a central nervous system hemangioblastoma and 16 had evidence for retinal hemangioblastoma that we could follow on study the overall response rate uh in renal tumors in uh this study with this agent was uh close to fifty percent uh these responses uh at least at the time of this analysis were all partial responses so we were not curing patients which is a hard difficult bar as you know because uh you you know you're never really going to change the german alterations and the predisposition to tumors but we were very very happy to see that half the patients had objective rhesus defined partial responses when you actually looked at how many patients had regression in their tumors much larger proportion 92 person had some degree of tumor regression knowing what we do about the way these uh this particular class of drugs work it is very likely that we'll see the response rates uh increasing overall but what's key here is that a very very overwhelming majority of patients did develop or did exhibit tumor regression this graph illustrates how we manage to alter the natural history of these tumors on the left side you will see the growth curves of these tumors that we're very very carefully followed pre-treatment for years on on many of these patients and the natural history is one of inexorable growth in the absence of intervention so the intervention usually until the study was surgery which would occur when the predefined criteria were met but you can see when we introduced belzede fan the vast majority of tumors either didn't grow at the same rate or many of them actually started regressing we talked a little bit about durable responses when dr mcdimmer is up here in the podium a few minutes ago at least as of now the responses with this agent seem very very durable at the time of this analysis with a median follow-up of around two years 89 percent of the patients remained on study and as you can see from the swimmer's plot most of them had ongoing clinical benefit i'm going to show you a couple of cases of the kind of patients we treated on the study and why are these drugs likely to make a really significant impact on how we treat this group of patients the first is a 45 year old woman who was diagnosed at the age of 34 with vhl when a left-sided renal tumor was identified she underwent a partial nephrectomy and were continued to be surveyed subsequently when she came to us she was very desirous of you know avoiding additional surgical procedures uh came to us with bilateral renal tumors the largest of which was around 2.6 centimeters so heading towards surgery she also had a couple of pancreatic neuroendocrine tumors and some cnsc angioblastomas shown here is a fairly large close to the hilum renal tumor in the left kidney and a couple of renal tumors in the right kidney all of which very very clearly and rapidly regressed following initiation of belgium fans so clearly at this point in time this patient does not need surgery at best i'm sorry at worst we have set the clock back by several years so it's unlikely that this patient would have needed would need surgery as quickly as she would have in the absence of this intervention we're also seeing very impressive responses in non-renal lesions in pancreatic tumors we see an overall response of 77 including regression in 90 of patients with pancreatic neuroendocrine tumors and around a third of patients with cns emangioblastomas have very clearly demonstrated regression these tumors are a little harder to follow and i suspect the true response rate's probably a little higher but this is what we found in the study uh i'm going to show you a second case here of a 30 year old man diagnosed with vhl the age of 12 uh you know very very difficult uh in our life for somebody who gets diagnosed at that early age with tumors everywhere i mean he had tumors in every organ you can conceive over the years he had to undergo multiple laser cryoablation of laser and cryobalations of retinal hemangioblastomas and had bilateral vitrectomies he's had seven no less than seven surgeries to facilitate resections of hemangioblastomas in the cns so you can imagine the impact these procedures have had on the quality of life of this this patient he came to us with bilateral multifocal rcc that we're heading towards the surgical threshold and new multiple cerebellar and cns enantioblastomas on the top panel we show you two hemangioblastomas one in the thoracic spine and one in the left cerebellum uh we work very closely with dr prashanti tiboyana and dr kareem zaglul neurosurgeons at the nih in the management of these patients and i'm glad to say at least in this case digital burner services will not be needed uh you see very very clear regression uh in both the tumors uh illustrated uh in on the slide ocular lesions contribute significantly to the mobility of patients with vhl many patients you know go blind and the patient are presented previously was blind in both eyes because of multiple retinal hemangioblastomas for the first time our ophthalmologists dr stu and henry wiley who worked very very closely with us in the management of these patients told us that they've seen impressive regressions of hemangioblastomas in the eye with a systemic agent so far there's nothing they've tried that's worked but we see very very predictable very uh you know impressive regressions in hemangioblastomas which this with this drug so one of the key goals of developing a drug like this would be to try and delay the need for surgery or obviate the need for surgery altogether and and this graph illustrates a little bit of what we've achieved on that front uh with this drug to the left of the solid black perpendicular vertical line that you see are the black dots that indicate surgical procedures in patients with vhl before belzodefan before they receive belzora fan and you can see a number of black dots so these number into the hundreds over the last several years in fact if you just look at the preceding two years which is approximately the length of follow-up we have on therapy for these patients you still see several procedures that these patients have had to undergo following initiation of belgium fan we only had three procedures that were needed in these patients so short follow-up but early indications are that we may actually be impacting how we manage these patients and minimizing the need for surgery in these patients i also said that it would be good to have a drug that was well tolerated and this drug fits the bill certainly far better than the wedge of targeted agents too while most patients had side effects most of the side effects were mild and manageable the most common and very predictable side effect because it follows from the biology of hef2 and how this drug targets that pathway was anemia anemia is mostly uh seen uh in a few weeks after we initiated therapy and tended to stabilize over time most patients could be managed very effectively without a need for stopping or discontinuing the drug patients were managed either expectantly or occasionally with erythropoietin and even more rarely with blood transfusions so most of the side effects were very very mild fatigue being cheap amongst them but most patients were able to lead a lifestyle comparable to what they had before they initiated therapy as you probably aware these data were recently uh presented in the new england journal of medicine as you're probably also aware these data led in august of 2021 to the approval of this agent for patients with almond confined tumors associated with vhl so as a result of these developments we now have an fda approved systemic therapy for the management of vhl associated tumors for the first time and implications clinical implications of this approval are that some vhl patients can now be managed medically and i emphasize the word some because i think we have to be very careful about whom we treat and how we treat them i look at this agent as being a compliment for conventional management strategies like surgery and triabulation and so on and so forth and i do believe that in the long run you will see a lot of patients avoid a delay surgery as a result of this this treatment and treatments like this i will also emphasize that while it's tempting to have everybody who has access to this drug treat patients with vhl with this drug uh care of the vhl patient is still very difficult and requires a very dedicated and experienced multi-disciplinary team we still have a lot to learn but i think this is a very promising beginning in treating vhl patients this drug has also shown efficacy in patients with advanced metastatic sporadic clear cell kidney cancer and shown here is a waterfall plot from a study dr shuerry conducted it's a phase one two study of this agent uh showing you know promising activity which has led to the development of uh randomized phase three study in previously treated patients with metastatic kidney cancer patients are randomized to this drug versus evaluation the trial is completely approval and we're waiting to read out the data so i i think we can learn from the foregoing you know slides that understanding the vhl pathway has allowed us to effectively intervene in patients with both sporadic uh forms of clear cell kidney cancer and vhl associated tumors uh a number of other hip to alpha inhibitors and now in early clinical development and we and others are trying to figure out how best to improve upon the benefits of have to alpha animators that we've gleaned so far from the studies i just presented i'm going to spend the next few minutes talking about papillary kidney cancer which is the second most common form of kidney cancer until recently there were no effective forms of treatment for this this this entity or this group of entities i must say as i'll point out in a minute or two the first dedicated papillary kidney cancer study to show a clear benefit for any intervention was this study called the paper study led by dr samantha paul and others which showed a superiority for caboz antony versus synerton in patients with metastatic papillary kidney cancer unfortunately the median pfs was only nine months in the overall response rate only 23 percent and we and others are hopeful that by understanding the biology of these tumors better we may actually be able to improve these numbers and i'll show you a couple of examples of how we may do that we we know that gaba zantner is a met as well as vegfr inhibitor going back a few years uh we and others uh conducted a study with another similar agent called phretinib which was the first in class met inhibitor evaluated in patients with kidney cancer it also had a vegetarian it also could target vegfr as as shown here uh several people uh that are involved with the treatment of papillary kidney cancers and dr schweiger dr mcdermott were all involved with the study and what we learned from the study was that just as with the patmet study not a lot of patients benefited from the study if you took all comers with papillary kidney cancer however if you look at patients with germline metal alterations really the population which you would expect most to benefit from a met in a bidder you saw a much higher response rate a response rate of 50 small numbers but regardless higher response rate while if you didn't have a met alteration your response rate is only nine percent so early indications that uh if you had a met mutation you might do much better with a meta-emitter other studies against small studies have confirmed this observation uh there's a study from europe looking at krizatnap we have a study with cab matineb which has shown very very similar results and extended the data that we have regenerated with this study more recently investigators at the memorial sloan-kettering cancer center have looked at cabozen combination of nivolumab and is starting to show some um you know promising activity in patients with papillary kidney cancer we still need to figure out who are most likely to benefit from this approach they present some you know early molecular data that suggest that some subgroups may benefit uh from this approach more than others and it's these kinds of studies that we really need to move the field forward the story with papillary kidney cancer however is a lot more complex than some of the for mentioned studies suggest papillary kidney cancer is a very heterogeneous group of malignancies it's not one entity just as we say kidney cancer is not one entity uh a papillary kidney cancer is not one entity a type 1 papillary kidney cancer is a relatively homogenous group of malignancies based on both the molecular changes underlying this entity and the histologic parameters that characterize this subtype of cancer however the entity that we've traditionally called type 2 that we like to refer to now as non-type 1 papillary kidney cancer is it's really a lot more diverse and a variety of different subtypes with in a diverse area of alterations have been identified and we've worked on this very very closely with our you know wonderful pathologist dr maria marina who's been telling us for years don't treat all paper kidney cancers the same and she was right because when we looked at the molecular profiles underlying these tumors through the tcga analysis we found that there were at least four distinct subtypes of kidney cancer and these molecular subtypes segregated with outcomes as well i'm going to focus today on one particular entity heterotrolymitis and renal cell cancer i won't go much into the clinical description of this entity because dr linhan already did but suffice it to say that this is an entity that occurs because of inactivating mutations in the fuminate hydrotest gene and the germline these patients have a very aggressive form of papillary kidney cancer and until recently there were no data from prospective studies to guide therapy and most of these patients died very quickly after diagnosis of metastatic disease by understanding the pathway that led to kidney cancer following loss of human hydrotase we were able to come up with a strategy to target uh effectively uh what we thought were key aspects driving this tumor and we used a combination of beverage system map and a lot of a wedge of targeted antibody and an egf receptor inhibitor to try and see if this combination would effective in this tumor we conducted a phase two study looking at both patients with hlrcc and sporadic papillary kidney cancer because some of those patients share some characteristics with hlrcc patients uh two independent cohorts treated identically with bevacizumab and latino skip over the slide and what we saw was that in the hlrcc group the overall response rate with this combination was 72 percent uh mind you this is a group that was not very responsive to treatments previously so treatments that were typically effective in that era in patients with advanced clear silicate cancer didn't do much for these patients and many of the patients who came onto the study were actually pretty treated with those agents like senator mitsapunov so we were quite happy to see a fairly high response rate we also noticed that the vast majority of patients who went on the study developed some degree of tumor regression once again durability is a key question and patients treated with this regimen had durable responses at the time of this analysis the median duration of response was 19.3 months and several patients after five six years still remain uh on the study in remission the median period first is 21.1 months this in a disease where before these treatments became available the overall survival was somewhere in the one uh to 12 months to 16 month range a couple of examples of the kind of patients we treated and you know saw some nice results with in this on this trial first is a 58 year old man who presented with left flank pain underwent a radical and effective uh refectomy with lymph node dissection for a large tumor uh astrology was consistent with the type 2 papillary kidney cancer and and germline testing revealed a pathogenic fh alteration he developed metastatic disease soon after his uh kidney cancer kidney primary resection and came to us with extensive retroperitoneal adenopathy as well as the mediastinal adenopathy and tumor deposits in this so as uh so fair amount of disease following initiation of treatment very rapid response in most of these areas with there after following four months of therapy very very little disease as you can see left the patient stayed on study for more than 18 months and eventually progressed a second case 33 year old woman again with a diagnosis of hlrcc with extensive hepatic meds treated again with this regimen you can see how significant the regression has been and how durable the regression has been shown here on the right side are regression of the hepatic mets two years following initiation of therapy patients remain on therapy for close to four years before eventually progressing we made some gains in treating this this condition but we want to do more we're not curing a lot of patients even though we see some durable responses and with a view to expanding on the you know gains we've made with this regimen we've opened a new study which combines uh this doublet with actualizamab pdl1 inhibitor to try and see if we can improve the results we have with this with this combination so i'll end there by saying that while papillary rcc is a very heterogeneous group of malignancies by understanding the distinct molecular pathways that drive individual subtypes of papillary kidney cancer we've started to make some headway in effectively treating at least some of these types and we and others continuing our laboratory efforts to try and expand this to other forms of papillary kidney cancer where we haven't been able to make the same kind of gains as the ones in which i've discussed so far last but not the least we have a large group of people aiding in this effort both within and outside the nci and without you know this very talented and committed group of individuals we'd never make the kind of progress we have thank you and i'll stop there thank you thank you very much and i mean i'm i'm completely blown away by the science behind all this and by the advances that we've seen and you've heard this morning well i don't know it makes my knees weak to think about you heard this morning from from dr mcdermott some complete responses in patients with advanced disease we didn't have anything before and you heard from dr srinivasan some dramatic response some complete responses in patients with papillary which was you know considered horrible and untreatable sort of and you also heard from dr chenonvas and don't forget this you heard from dr srinivas and also in vhl this is the first hit responses in kidney right responses in our in kidney we think of surgically all right i think this is just the beginning he also showed you some that met that hereditary papillary there he showed it was kind of buried in a slide but their responses in kidney tumors in patients with that type of kidney cancer papillary with that gene met there now we're not home yet you know they're not you know complete responses and make them completely go away but the first evidence that you could really treat tumors even in the kidney so i think as urologic surgeons you know we got a lot to think about here but uh but i think we're getting a lot of help from our colleagues working on understanding how these tumors work and working on developing these therapies so are you all going to be able to pull up the my slides again while they're while they're doing that mine was the first talk i think just for the for the follow-up questions if we can do it we will if we want it's fine uh so let me go back though just a surgical question uh dr ball you know you showed us some remarkable advances surgically and managing these i know you can do almost anything robotic but here we are in 2022 when you're we're doing those cases i mean for example you know old days we we used to clamp and slush you know so when do you clamp today you know with you can do anything but when do you clamp and and also when you just say look it's safer let's just take this kidney out you know two questions uh good questions and and and tough questions in in many ways um i think there are two main reasons to clamp uh one is uh one is hemorrhage but two is to be able to visualize uh your tumor and resection plane and have a good oncologic result and certainly for a deep tumor one that's abutting the sinus i i almost always clamp to prevent the first but then able to make sure i have a good margin because we you can see it's particularly deep sometimes tumors are not perfectly around they can have lumps or bumps and if you uh if you leave a piece of tumor behind then you've not done the patient any good uh and then the second you know the aua guidelines have really laid out pretty well when we can think about radical nephrectomy if a patient um is going to have um has a higher oncologic risk tumor and is predicted to have a gfr of you know over 45 and that's that's a patient where radical is on the table and we can we can certainly think about that and um while we certainly underutilize partial nephrectomy and and in some places among you know cancer centers and tertiary scenarios we we may be over over utilized rather than underutilized partial nephrectomy so those are some of my thoughts okay all right well in other words be safe than sorry we want to save kidneys but we don't want to save the cancer and leave it have we come back and and bite them so living to fight another day with one kidney is better than developing metastatic disease so we're pretty conservative on that dr ball you presented a case of bilateral tumors one side was chromophobe the other side was rcc a clear cell you opted to go for an enucleation and then wide excision given the high concordance histological concordance of 90 for synchronous bilateral tumors how frequently do you do a bilateral biopsy that's a really good question fantastic question you know i i think we can't take for granted uh if just because we see something on one side that it's the same thing on the other so i i will often utilize biopsy again when it's going to change management if we take out a tumor that's an oncocytoma on the other side you know i'm on one side i'm probably going to biopsy the other because if it's oncosatoma that's going to change management i may not offer that patient any treatment and do active surveillance um or if it's a it's a deep tumor that maybe is a radical and a biopsy that tumor same as if it were the you know presenting with one tumor and one kidney um when when it's really going to change management is when i utilize it we we always say kind of we have a sort of a thing at our place that you know you don't second-guess the the general in the field in other words the surgeon doing the case and uh so you know as dr ball would say we've had people with bmf anka sorry bar lighter multifocal onco but we're not so sure you know we make sure we had one recently there was uncle uncle uncle on one side aka uncle clear on the other and that clear just about bit us it got deep and it got into the renal vein we got it out guys don't find so far but you know that was the surgeon managing the patient said i'm worried about that i'm not sure about that now we'll do sesta mibi dr baugh would take he showed that system maybe sometimes helps us but even that we're a little little sort of uh sort of uh you know kind of careful careful about doctor dr avastin just in the last minute here you talked about this miracle drugs i mean this incredible thing with belzuda fan just i got a couple patients here real quick i got a 22 year old so our urologic surgeons here they're seeing a 22 year old with this disorder got a two centimeter mass in the kidneys she's not had female not had any surgery two centimeter uh treat them watch them we wouldn't do surgery because there's not three but you know what do you think i i got two patients and then i got a 44 year old who's also got a two centimeter he's had two surgeries already okay his renal functions a little down not much a little bit and you know he doesn't want more surgery okay those two patients real quick in closing so assuming there isn't any other overriding reason to treat this patient like a symptomatic energy bloodstream or near symptomatic imagioblastoma in the spine or some other reason assuming that the decision is going to be driven by what we see in the kidney i might be inclined to watch the 23 year old a little longer because i think i think there's a shelf life to these agents i'm not sure that we can treat them for life with this agent fear is that eventually you'll develop some resistance although i don't know that at this point so i'd be i'd be very judicious in offering somebody who may not need it right away it may take years for her to get too close to three centimeters i may offer it closer to the time she's uh reaching three centimeters uh on the other hand if somebody who has already had two surgeries and we want to avoid third surgeries at any cost and have a tumor that's you know heading towards the surgical threshold i may be a lot more inclined to offer that person so i think that i presume the consensus of the group up here also wouldn't be we've kind of got a lot to learn we have a wonderful tool we're thrilled about is approved by the fda as dr nevastin said based on this wonderful trial and uh but uh you know in course you got to think about the other things with those vhl people not that that common but if you do when you do see them you know the brain which you know you treat also in the pancreas so i have to think together on that but anyway all right we're at the 12 o'clock hour and i want to really thank uh my colleagues here that made so many contributions to this field we're so thrilled that they came thank you dr mcdermott thank you dr shanawassen thank you dr ball for coming we really appreciate it i know i learned a lot and if the audience learned as much as i did then it was a great session thank you very much 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