 Right, so I'm going to talk about the role of surgical resection in the management of advanced kidney cancer It's kind of strange You know, there's a saying in Texas You know sort of like closing the barn door after the horses have already left Doesn't make a lot of sense to do surgery in the setting of metastatic disease But I hope to convince you and show you that there definitely is a role Both for the resection of the primary tumor as well as for potentially resection of metastatic disease and in fact arguably surgery or You know the old heel with steel is better than any chemotherapy that we have to offer you If we were having this meeting ten years ago, I wouldn't have a whole heck of a lot to talk about I could actually show you this slide and then go sit down because we really had nothing to offer patients with metastatic disease Patients who had localized or locally advanced disease were largely treated with nephrectomy and those patients who presented with Metastatic disease usually underwent nephrectomy because we had nothing else to offer you And then then we get systemic therapy usually with a immunotherapy that was Largely ineffective and the median survival for patients with metastatic disease was about a year But it's a new era in the treatment of kidney cancer There have been somewhere around 12 to 13 new treatments that have been approved for the treatment of kidney cancer in the last 10 years And so the real question is is there still a role for the first surgical resection of patients who present with metastatic disease in light of all these novel therapies that we have that have prolonged patients lives What we do know about these agents is that they are not home runs they don't cure people Their base hits at best But we do have plan a plan B plan C and D and so on But at the end of the day patients ultimately become resistant to these therapies and ultimately they will die of their disease So what is the proper integration of surgery and systemic therapy in the setting of patients who present with metastatic disease? Well, I like to illustrate this conundrum with two cases that really show How difficult it can be to select appropriately for surgical resection and patients who present with metastatic disease? First patient is a 62 year old white male who presented with blood in his urine He had some minor medical problems some minor previous surgery He had a performance status of one so performance status just basically means how active you are with your cancer So performance that is zero means you have absolutely no symptoms related to your cancer performance status one as you have some symptoms But it doesn't affect your daily life Performance status two means you spend less than 50% of your day sitting or lying down as a consequence of your cancer Performance status three means you spend more than 50% of your day lying down or sitting down because of your cancer Performance status four means you're bedridden and performance status five means you're dead So this patient had a performance status of one and you can see on this CAT scan on the right kidney This locally advanced tumor involving the right kidney and you can see these little nodules in the lung bilaterally That represent metastatic disease to the chest So this patient had some anemia had an elevated LDH which is a blood test that we get to sort of give us a measure of overall disease and The remainder of the labs were normal and the patient had no other evidence of metastatic disease aside from the nodules that were present in the lungs So the patient underwent what we call cytoreductive nephrectomy, which means that patient underwent surgery to remove the primary tumor Here's the pathology Follow-up scans at six weeks showed some modest progression of their pulmonary disease So basically they couldn't get any therapy for six weeks while they were recovering from surgery and we expect their metastatic disease to grow But the patient was ultimately started on synitinib, which is one of the new targeted therapies. They required a dose reduction due to toxicity Ultimately at 14 months out and I remember what I said before was the median survival was one year This patient's already lived 14 months after surgery They were changed over to Everleamus, which is an mTOR inhibitor and now they're actually over three years out and still doing well In contrast, this is a 73 year old white female Who presented with fatigue and anemia? She also had a performed status of one some minor medical comorbidities and She had basically similar labs to the first gentleman that I presented to you She too had a locally advanced tumor involving her right kidney and bilateral nodules in the lung that represented metastatic disease So she underwent a right radical nephrectomy and at the time of surgery We actually noted a mass in a right fallopian tube, which turned out to be metastatic kidney cancer she also had some positive nodes and On final pathology her tumor demonstrated what are called sarcomatoid and rabdoid features and basically that just means a Very aggressive form of kidney cancer that wasn't recognized on the imaging that was done prior to surgery She had three out of ten lymph nodes that were positive But all of our surgical margins were negative meaning we removed all disease present in the abdomen She returned one month later with a performance status of four. Remember that means she's completely bedridden She was admitted through the emergency center for failure to thrive her labs were all out of whack Here's her scan. She has massive recurrence in the retroperitoneum. Here's tumor involving her liver and her vena cava There's tumor over here involving the ribs There's met to the liver Again massive recurrence despite having negative margins And ultimately the patient never got any systemic therapy no chemotherapy whatsoever when she died of disease 45 days after surgery Arguably did not benefit at all from cytoreductive nephrectomy So you can see that these two patients presented exactly the same and yet had two very different outcomes and the question is is there any way That we can avoid That second scenario Well the group from UCLA were one of the first to demonstrate the benefit of surgery and again, I would argue that Back in the day surgery was offered largely because we didn't have anything else to give you But they noted that those patients who underwent nephrectomy or even better Nephrectomy followed by immunotherapy had a significantly better outcome than those patients who were treated with their primary tumor in place So this prompted the conduct of two randomized trials one done in the United States one done over in Europe Where patients were randomized to radical nephrectomy followed by interferon, which was the systemic therapy du jour versus interferon alone and Both the European trial shown here as well as the United States trial shown here Demonstrated that patients who underwent cytoreductive nephrectomy had a doubling of their survival relative to patients who were treated with their primary tumor in place And it suggested that somehow some way this primary tumor was Influencing the overall behavior of their disease and that by removing it patients could have a better outcome well the group again from UCLA noted that In a furan is largely thought to be a rather ineffective therapy It basically makes you feel like you have the flu all the time and Response rates are only about 5% And so they said well, you know If you could offer patients of better therapy and in their minds at the time Interleukin 2 was a better therapy Surgery followed by better therapy would result in better outcomes for patients And in fact they plugged in in their retrospective database They plugged in the entry criteria for the SWAG trial the trial done in the United States And they noted that patients who received dial 2 arguably a better therapy Did better following nephrectomy Well as I said at the start of this talk, we now have 13 better therapies, so Surgery followed by all these different better therapies should really result in a better outcome for patients What's interesting though is that's not we're not practicing what what we preach You look at this slide This shows the utilization of cytoreductive nephrectomy in the United States over time The new targeted agents were introduced in 2005-2006 and you can see right at that time cytoreductive nephrectomy was on the decline So while we believe that the research shows us that surgery followed by better systemic therapy would result in better outcomes It would appear that in at least in the community People don't believe that they think that systemic therapy alone is the best option for patients And that's also shown in this Mayo Clinic study where you can see the blue bars in the top graph Decline over time showing the decreased utilization of cytoreductive nephrectomy in the era of targeted therapy Well, why would you not want to do a cytoreductive nephrectomy? Well, I can tell you that having done literally thousands The morbidity and the mortality potential is significant. These are big operations It's only been proven beneficial in combination with interferon, which arguably is an inferior therapy that we don't use really anymore It's possible that the patient may spend the rest of their life on this earth recovering from that surgery And as I showed you in that second case Patients may actually have rapid disease progression after surgery never even get systemic therapy And maybe these new therapies result in primary tumor regression. So maybe there is no role for cytoreductive surgery anymore What are the potential benefits? Well, it can alleviate or prevent local symptoms related to the primary tumor. Although in my experience, that's quite rare It may eliminate a main or at least one source of further metastatic progression Meaning that once the tumor is gone, it can no longer send cells out where out into the rest of your body It may alleviate systemic symptoms related to cytokines or perineoplastic syndromes and With one swipe of the knife we can actually remove more than 75% of your tumor burden in one operation Despite using this modality for literally decades. We have absolutely no idea how it even works We do it, but we don't know why patients benefit from it. Is it a reduction in the major portion of tumor burden? Is it some sort of immunologic phenomenon where somehow surgery exposes new antigens or removes some sort of immunologic sink? There have been hypotheses that perhaps it alters the metabolic milieu and that's somehow anti-tumoral Or perhaps it's some sort of endocrine or paracrine phenomenon where we're removing a tumor that is secreting growth factors That ultimately cause disease progression Well, there are data that indirectly give us some hints as to how cytoreductive surgery works We did this study a retrospective study looking at patients with non-clear cell versus clear cell histology And what we noted was in the setting of non-clear cell histology Cytoreductive surgery really did not demonstrate a benefit So from my perspective that tells me that just removing tumor is Not the answer. There's got to be more to it than that. Otherwise, we would have seen a benefit in non-clear cell histology And these are some intriguing data out of that SWAG study that I showed you the randomized trial looking at nephrectomy followed by interferon versus interferon alone And what they looked at was the patient's postoperative creatinine, which is a measure of kidney function and they categorized patients as anyone who had a change in their creatinine an increase in their creatinine which Would be translated into a decline in renal function and compared them to patients that did not and And they noted that the patients who had a decline in their serum or it's hard an increase in their serum creatinine had a significantly better survival relative to patients that did not and suggested that perhaps this Relative azotemia or relative renal insufficiency was somehow anti-tumor So back in the day we used to see patients and we'd look at their tumors under the microscope and we'd see these tremendous lymphocytic infiltrates where their immune system was Infiltrating the tumor would say wow this guy is going to do really well his immune system is killing this tumor and In fact, we were exactly wrong those patients as shown here who had marked Lymphocytic infiltrates did the worst relative to those that did not and now with further research We know why that is Because the tumor cells were actually turning off the immune system as the tumor attacked it We now know that the tumor expresses molecules that interact with the immune system and can shut them down And actually that is the basis for the novel new immune checkpoint blockade inhibitors that we're using in the clinic Where we can block that interaction and no longer allow the tumor to shut down the immune system Is there any clinical evidence for the systemic influence of the primary tumors such that removing it would remove that influence while Kidney cancer is famous for perineoplastic syndromes where patients present with a whole host of different Symptoms that are completely unrelated to their primary tumor, but are related to growth factors that are secreted by the tumor We've all heard of spontaneous regression of metastatic disease, which I've seen twice in my career Reportedly it happens one to two percent of cases and It's only associated with clear cell histology and As I showed you in my second case Explosive progression of metastatic disease can also follow surgery Thankfully, it's rare, but when it happens, it's memorable So is there any role for seder-reductive surgery in the setting of targeted therapies these new targeted therapies that we have well They're currently our two randomized trials trying to answer that question This is a trial called the Carmina trial which currently is ongoing in France where parents are Patients are randomized to an effrectomy followed by synitinib versus synitinib alone This trial has been going on for 10 years. They still haven't reached their accrual goals. And in large part I think it relates to the fact that Most people believe that seder-reductive surgery does still play a role. And so patients are unlikely or unwilling to be randomized And arguably when this trial finally does read out The question is Will it even be relevant will we even be using synitinib to treat patients with metastatic kidney cancer? Because it's going to be probably another five to seven years before this trial actually reads out if it ever does Another trial that's ongoing or was ongoing is this trial looking at the timing of surgery in the setting of systemic therapy So basically patients were randomized to upfront surgery followed by synitinib Versus two cycles of synitinib followed by surgery followed by continued synitinib So it doesn't ask the question should we do surgery it asked the question when should we do surgery? But again, the problem with this trial is that it closed because no one was entering patients So in the setting of targeted therapy, we have no level one evidence to suggest that surgery plays a role The problem is I have clinic Wednesday. I can't wait for these trials. I have patients that are going to show up with metastatic disease What do I tell them? Do I tell them that there is no role or we don't know what the role is? Do I enter them in a clinical trial? How do I manage them? Well, there is retrospective data that gives us some clue as to whether or not surgery does play a role in the setting of targeted therapy In the setting of metastatic disease These are data from the expanded access trial that was conducted by Pfizer when synitinib was being developed And they looked at patients who had prior nephrectomy not necessarily site reductive nephrectomy But had their kidney removed at some point in the past and compared them to patients who were treated with their primary tumor in place And you can see that there was a doubling and the response rate for patients who had had a prior nephrectomy And those patients who had a prior nephrectomy had a improved progression free survival and an improved overall survival Relative to patients who were treated with their primary tumor in place. Their survival was almost double Admittedly retrospective, admittedly biased, but does give us some indication that controlling the primary tumor does play a role in the management of these patients These are data from the Dana-Farber Institute Where they looked at patients who presented with metastatic disease with their primary tumor in place And they noted again a doubling in the survival for patients who underwent site reductive surgery prior to systemic therapy Now again the reason why these patients in the in the no group didn't have surgery is suspect They were probably poor surgical candidates. They probably had advanced disease But it still gives us some indication that controlling the primary tumor is important in the setting of metastatic disease And this is data that we published more recently looking at the SEER database, which is a large collection a national collection of Patient data and we noted again that those patients who had site reductive surgery had a significantly better outcome in the setting Or the era of targeted therapy although the SEER database doesn't actually tell you what specific therapies those patients received That's not to say that everyone should have site reductive surgery as I showed you in that second case that I presented that I made the wrong decision in that woman and She died as a consequence so patient selection clearly clearly is critical in Employing surgery for patients who present with advanced disease One of the first groups to demonstrate that was a group out of Tufts University Where they noted that those patients where you could remove more than 75% of their tumor burden Absence of brain liver and bone metastases Good performance status and clear cell histology did well with site reductive surgery and then they use those criteria prospectively and Selected 28 patients for site reductive surgery deferring 61 patients who didn't meet the criteria and 93% of those patients went on to receive systemic therapy with an excellent response rate in the era of IL-2 More recently we looked here at MD Anderson at 566 patients who were treated with site reductive surgery between 1991 and 2007 And we compared them to a group of patients who received only systemic therapy alone with their primary tumor in place And we compared outcomes Now the bent here at MD Anderson is to treat patients with surgery if at all possible So you can imagine that the patients that we did not treat with surgery were the worst of the worst And in our hands the worst of the worst survived 8.5 months So we went back to our surgery group and we said okay If we did surgery on you and you did not at least survive 8.5 months, then we probably didn't help you with surgery And then we asked the question well, what factors what clinical factors can we use to predict your survival after surgery? and What we noted was that those patients who presented with a low serum albumin an elevated LDH the presence of liver metastases Symptoms that were related to metastatic disease such as bone pain cough related to pulmonary metastasis and so forth and Nodal involvement meaning involvement of the lymph nodes by cancer either in the chest or in the abdomen and A locally advanced t-stage all of these factors Were associated with an adverse outcome And what we noted was in our study that if you had three factors or less Your outcome was better than the people that received only systemic therapy But if you had more than three of these factors your outcome was the same or even worse Than the patients who received systemic therapy alone And so now prospectively we use these criteria to better help us select patients for surgery and Help us avoid the consequences associated with that second case that I showed you This is another study out of Canada Where they looked again at factors that predicted for outcome and patients who underwent cytoreductive surgery and came up with some Very similar findings the presence of anemia elevated calcium levels elevated white blood cell levels elevated platelet levels poor performance status and a diagnosis to treatment time of less than one year meaning that you Presented in gut treatment in less than one year from from your presentation all of these were associated with outcome So with regards to cytoreductive nephrectomy Cytoreductive surgery does improve survival in properly selected patients The goal of surgery should be should be to remove the majority of tumor burden with one surgical procedure Poor performance status the presence of liver brain or bone mats The presence of nodal metastases and the presence of sarcomatoid histology all predict a poor outcome And in that situation those patients are probably best served by receiving upfront systemic therapy Followed by possibly delayed surgery if they respond So I wanted to talk just a very little bit about surgical resection of metastatic disease So this is not resection of the kidney But resection of metastases be they brain mats bone mints lung mints what have you So a little bit about the epidemiology of metastatic kidney cancer 63 to 65,000 patients are diagnosed yearly of those 30% present with metastatic disease and even those patients who present with localized or locally advanced disease 30 to 40 percent of them are destined to ultimately get metastatic disease so you can see That metastatic kidney cancer is a real health problem 13,000 patients per year die of metastatic kidney cancer and The rate of kidney cancer is increasing by 2% per year What are the challenges associated with the management of metastatic disease? It is not responsive to most chemotherapies It's not responsive to radiation therapy at all. In fact radiation is only used for paliation of pain The remark the minority of patients respond to cytokine therapy, which is interferon interleukin 2 the old systemic therapies Even with the new targeted therapies complete responses are rare these agents do not cure they control but they don't cure and I would argue that surgical therapy when possible Represents the best form of treatment and is better than any chemotherapy that my medical oncology colleagues have to offer Heal with steel as they say is certainly the best option for patients with metastatic disease when it's appropriately applied So just a couple studies that have looked at this and the biggest problem with these studies that you have to take with a grain of salt Is that they're all retrospective? Meaning that we looked back at our experience as opposed to taking patients Prospectively as they walk on the door and randomizing to surgery versus no surgery Which probably can never be done because there's just not enough patients to actually complete a trial like that So in large part patients who underwent surgery. There's a selection bias. They underwent surgery because they had favorable disease Probably had good performance status We're very eager to proceed with surgery and so all of those things could impact the outcome So there are numerous studies retrospectively published in the literature, but the outcomes are really impressive Here's one from Sloan Kettering where patients who underwent a complete metastasectomy the five-year overall survival rate was 44 percent Almost half of the patients were alive five years after surgery, which is unheard of in the setting of metastatic disease particularly in that era Here's another study again out of Sloan Kettering where any patient who had any metastasectomy the five-year overall survival rate was almost 50 percent This is a study out of the Mayo Clinic where they looked at over a thousand patients any patient who had a metastasectomy five-year overall survival 44% very impressive And again another study out of the Mayo Clinic where those patients who could undergo complete metastasectomy their five-year cancer specific survival So that's not even overall survival. It means being disease-free five years out from the surgery 45% So in highly selected patients where sir aggressive surgical resection can be accomplished The outcomes can be excellent So just to delve into a few more of the details This was the study out of Sloan Kettering two hundred and seventy-eight patients 57% of patients had lung metastases 19% had bone Complete resection was accomplished in 59% incomplete in 41% And in patients who had a complete metastasectomy their five-year overall survival rate was 44% This is from the Mayo Clinic 727 patients again, you can see the distribution of metastases They were able to accomplish a complete resection in 26% the five-year overall survival and the cohort was 15% This is a more recent study out of Sloan Kettering 129 patients you can see the distribution of lung and bone metastases They were able to get a complete resection in 31% None was performed in 66% and when they compared the two the five-year overall survival for the group that had any surgery for Metastatic disease was 49% with a median survival of 45 months This was a study of more than 1300 patients with a variety of different metastatic deposits They did not report on whether or not the patients had a complete versus incomplete resection But they did note that any patient who had any metastasectomy their five-year overall survival was 44% And their median survival was 44 months, which is quite impressive relative to the group that did not undergo Metastasectomy where their survival was only 20 with 22 months And then lastly, this is the more recent study out of the Mayo Clinic 887 patients Complete metastasectomy was accomplished in 14% of the patients They looked at timing location number of metastatic sites and performance status relative to outcome and that's shown graphically So those patients who had a complete surgical resection their median survival was 4.8 years versus those Without complete resection the median survival was only 1.3 years shown graphically here And in patients who only have lung metastases, which is thought to be very favorable in metastatic kidney cancer Those who had a complete surgical resection median survival cancer specific survival was almost 75% And patients without lung metastases who underwent complete resection had a significantly worse outcome But still better than those that could not have their disease completely resected with a median survival of 32.5% Asynchronous metastases meaning they developed their metastases Distant from when they had their primary tumor those patients who underwent complete resection again had a significantly better outcome If you had two metastatic sites if they could be completely resected You did significantly better than again those patients who could not have complete surgical resection of their metastatic disease And that also held true for those patients who had even more than three Metastatic sites meaning like long bone liver or or other organs What is clear is that you should go in there? Trying to swing for the fences Meaning that the completeness of the surgical resection is the most important factor that predicts outcome If you go in with and they have five metastases and you only resect three you're probably not doing that patient of service So resection of complete metastatic disease was associated with the best outcome in all of these different studies Performance status is also important. It's important to operate on patients who are healthy and doing well And in this particular retrospective study performance status was a strong predictor of outcome with regards to metastasectomy And then finally this was a systematic review looking at all of these different studies and the role of metastasectomy You can see from all these different bars over here on favors metastasectomy side That all these studies were able to demonstrate that surgical resection of metastatic disease was associated with an excellent outcome in Properly selected patients So in summary complete resection when feasible I would argue represents the best option for selected patients It's better than any chemotherapy. We have to offer you Incomplete resection remains beneficial, but I would argue systemic therapy probably is a better option than just resecting part of the disease But we need to keep in mind that metastasectomy is a reasonable option in patients with solitary or Oligometastatic meaning very minimal metastatic disease Who are good surgical candidates? And so with that I'll close I'll be happy to answer any questions that you have and then we'll take a Break for about 15 minutes any questions at all Okay, why don't we take a break for 15 minutes and then we'll start with the second half of the program. Thanks very much