 So, I'm going to talk about the role of cyto reductive surgery or nephrectomy in the setting of metastatic disease. As we talked about earlier, stage means everything in kidney cancer and those patients who present with stage 4 disease, approximately 30% present with stage 4, a total of 50% will ultimately develop stage 4 in their lifetime. As they say, up until 2006 we really had no treatments for kidney cancer, therefore surgery played a major role in the treatment of all phases of the disease. But since 2006, a variety of different therapies have been approved for the treatment of kidney cancer, seven of them almost unheard of for the treatment of malignancy, including exitinib, which was recently approved back in January of 2012. So now we have a whole plethora of different treatments. In fact, it's almost an embarrassment of riches. We almost have too many therapies and it can be very challenging to decide when to employ which therapy and which setting, although this algorithm does provide some guidance. And we have numerous therapies that are certainly in the pipeline being developed as we speak. And as I said in my earlier talk, these are not home runs. They're base hits basically, because ultimately the treatment, the tumor will become resistant to the treatment and will start to grow and progress despite the treatment. So the question is what is the proper integration of surgery and systemic therapy in the setting of metastatic disease? So let me illustrate this with a couple of cases. So this is a patient of mine, 62-year-old white male who presented with blood in a urine, few comorbidities, diabetes and hypertension, had some previous surgery. Physical examination is unremarkable, performance status is equal to one, meaning there were some symptoms related to the primary tumor, but overall the patient was doing well. Here's the CT scan. You could see a locally advanced tumor involving the right kidney, as well as bilateral pulmonary nodules. Here's one here. Here's one here. Here's a small one here. So basically, locally advanced primary tumor with METs to the lung. Patient had some anemia, had an elevation in their LDH or lactate dehydrogenase, but otherwise their labs were within normal limits, bone scan and MRI of the brain are negative. So patient undergoes surgery to remove the right kidney. Here's the stage T3A N0M1. Here's a clear cell, grade four out of four. Follow-up scans six weeks out show modest progression of pulmonary metastases, meaning the pulmonary METs get slightly bigger. Started on synitinib, tolerated for a while, then had dose reduction at six months due to toxicity. Showed progression at 14 months was changed to everolimus and currently is stable two years out from surgery. Doesn't actually prove that cytoreductinifractomy helped, but it certainly didn't hurt in this case, and the patient is ultimately doing well. So let me show you another case. This is a 73-year-old white female who presents with fatigue and anemia, again, performing status one. She's got some minor medical comorbidities. Very similar story, bilateral pulmonary nodules, she's anemic, LDH is elevated, brain scan, bone scan, both negative. You can see that this is almost identical CT scan. Here's a locally advanced tumor involving the right kidney, another picture here, and then bilateral pulmonary metastases. So this patient undergoes right radical nephrectomy with RPL and D, there was a mass noted in the right fallopian tube, which we resected and it turned out to be metastatic disease. So she had positive nodes, T3aN1M1. There was some evidence of sarcomatoid and rabdoid features, which means just a very more aggressive type of kidney cancer, 3 out of 10 lymph nodes positive, all surgical margins are negative. So basically the exact same story as the first patient. This patient returns in one month with a performance status of four, and just to let you know, performance status of five means you're dead, admitted through the emergency center for failure to thrive, she's anemic, her LDH is through the roof, she's hypercalcemic, meaning her calcium levels are elevated. Here's her scan, massive recurrence in the retroperitoneum tumor involving the portal system involving the area where the kidney was resected, invading into the liver, and ultimately the patient never received systemic therapy due to poor performance status, and she died 45 days after surgery. Same exact case, same exact presentation, one had a great outcome, one I would argue not so great. So the question is, is there still a role for seder-reductive surgery in the setting of metastatic disease in the era of targeted therapy? These are historical studies, this is one from UCLA, and they were the first to demonstrate the importance of surgery. You can see that patients who just received immunotherapy without surgery did poorly. If they just had surgery and received no systemic therapy, they did better than those that received immunotherapy. But if they received a combination of nephrectomy followed by immunotherapy, their outcome was the best. So because of these data, there were two randomized prospective phase three trials that were done to demonstrate the role of seder-reductive surgery in the era of immunotherapy. One was done by SWAG here in the United States, one was done over in Europe by the EORTC, where patients were randomized to upfront surgery followed by interferon versus interferon alone with an endpoint being overall survival. And both studies, this is the EORTC study, demonstrated that the overall survival and time to progression was significantly better in the group that had nephrectomy followed by interferon versus those that were treated with their primary tumor in place. That's again shown here with the SWAG study. So patients who undergo surgery followed by interferon had a better survival than those patients who had interferon alone. Now interferon is a very historical therapy, not really used much in the treatment of kidney cancer anymore, and many surgeons refer to these trials as surgery followed by ineffective therapy is better than ineffective therapy alone. The group from UCLA took the criteria that were used to enter patients into the SWAG study and plugged it into their database where patients received interleukin-2, and their argument was interleukin-2 is an infinitely better therapy than interferon. And what they noted was that those patients who had nephrectomy followed by interleukin-2 a quote unquote better therapy had a better survival than patients who received nephrectomy followed by interferon. And so they concluded by saying if we just had better therapies, then surgery with better therapy is going to result in better outcomes. Well as they just got done saying, we have a whole host of different therapies that are purported to be better. And certainly the median survival for patients with metastatic kidney cancer has dramatically improved. It's greater than two years whereas it used to be less than a year. Yet in spite of that, what's interesting, this was a study that was published where they looked at the utilization of cytoreductive surgery, and you can see that right about the time that the targeted therapies were introduced in 2005, 2006, all of a sudden cytoreductive nephrectomy was on the decline. So while we can sit here and say that we believe that nephrectomy followed by better therapies is going to result in better outcomes, it doesn't appear to be believed in the general population of medical oncologists because the utilization of cytoreductive surgery was on the decline as a consequence of the introduction of those therapies. To be candid, we don't even really know how cytoreductive surgery works. Is it just a reduction in the major portion of tumor burden? Is it some sort of immunologic phenomenon where we're somehow exposing new antigens or removing an immunologic sink? Is it somehow altering the metabolic milieu where removal of the kidney results in renal insufficiency and results in an acidosis or something that's somehow anti-tumoral? Or perhaps the tumor secreting something that by removing it, we decrease the risk of disease progression or decrease the risk of metastatic progression. We really don't know how it works at all. So why not do surgery? Well, these can be very morbid surgeries and there is a mortality rate associated with it. It's only been proven to be beneficial in combination with interferon. It's quite possible that the patient may spend the rest of their life on this earth recovering from surgery, such as that second case I showed you. And patients may demonstrate, like I showed you in that second case, significant disease progression or morbidity that may preclude them from ever getting systemic therapy. And who knows? Maybe these newer therapies will result in response in the primary tumor and maybe we don't need to do cytoreductive surgery. Well, the French are currently testing that. This is a trial that's ongoing in France. It's the so-called Carmina trial where patients are randomized to an effrectomy followed by synitinib versus synitinib alone. It's a non-inferiority design, meaning at the end of the day, they'll be able to say that only receiving synitinib is not inferior to having surgery followed by synitinib. Doesn't mean it's better, just means it's not inferior if the trial is positive. They've had significant trouble accruing to this trial in large part because I think deep down most people believe that most patients should undergo surgery. And so the vast majority of patients that are being enrolled in this trial are probably borderline surgical candidates where it's not really clear what the indication for surgery is. The problem is, next Wednesday, I'm going to see patients in my clinic that have metastatic disease. And what am I supposed to tell them? Is there any evidence that doing surgery in the setting of metastatic disease for patients destined to receive targeted therapy is beneficial? Well, there is retrospective data. This is from the synitinib expanded access trial where patients were treated with their primary tumor in place and compared to those that had prior nephrectomy. Not necessarily cytoreductive nephrectomy, but prior nephrectomy. And you can see that the response rate was double in the group that had previous removal of their primary tumor. And in fact, the progression pre-survival and the overall survival was better in patients who had had a prior nephrectomy. Again, not necessarily a cytoreductive nephrectomy, but had their primary tumor removed at some point prior to receiving synitinib, their survival was better. And more recently, Tony Schwere from Dana-Farber did a retrospective review of patients who presented with metastatic disease, some underwent cytoreductive surgery, some did not. And you can see that there was a doubling in survival for the group that underwent cytoreductive nephrectomy, followed by treatment with targeted therapy versus those patients who were treated with their primary tumor in place. Admittedly retrospective, admittedly biased, because it's not clear why the patients didn't undergo surgery versus those patients that did undergo surgery. One would presume that the group that did not were probably not great surgical candidates, maybe had more burden of disease, had a worse performance status, et cetera. But it does provide some indication that doing surgery in the setting of metastatic disease is potentially beneficial, provided that the patient selection is adequate. And this is a study that we recently published from the SEER database, again demonstrating basically the same thing. As a side note, one of the potential benefits of performing cytoreductive surgery is potential involvement in this clinical trial, which I'm a PI of. This is so-called a DAPT trial where patients are randomized to receive an autologous vaccine made from their tumor, in addition to synatinib versus receiving standard of care, which is synatinib alone. As I say, this trial is currently ongoing. Here's the premise. Basically, you take the kidney out. You send it to the company. They isolate the RNA, and then they do a leukophoresis, which means to isolate white blood cells from a patient. They do something to those white blood cells. There's one of those if I told you I'd have to kill you kind of things. And then they post the RNA through those white blood cells and give them back to the patient as a dendritic cell vaccine. As I say, this trial is currently ongoing. We're all excited about it. But we'll see if this is beneficial. So I've told you about the potential benefits of cytoreductive surgery, but clearly it's not for everyone. In that first case, we could argue that maybe the guy benefited from it, but clearly in the second case, we chose wrong. So somehow, some way, we have to improve our ability to select patients for surgery. One of the first studies that looked at different criteria to select patients was this one out of Tufts, where they noted that those patients who had a greater than 75% reduction in tumor burden, the absence of brain liver or bone metastases, good performance status, and clear cell histology were most likely to benefit from surgery. And then moving prospectively, they used those criteria to select patients, and of almost 100 patients, they selected 28. 61 patients were deferred because they didn't meet the criteria. And you can see that 93% of the patients went on to receive systemic therapy, so presumably they did well after surgery. And their response rate was really an unheard of, 39% in the era of Interleukin II, where response rates are typically less than 15%. So moving forward, it was clear that the criteria we should use to select patients are good performance status, absence of significant comorbidities, the absence of brain liver and bone mets, large primary tumor, and the ability to resect the majority of that disease through a single surgery. If you do a biopsy, the absence of sarcomatoid de-differentiation, although to be honest with you, try and identify sarcomatoid de-differentiation on a biopsy is almost impossible, and the presence of clear cell histology. Those are the criteria we should use moving forward. The problem is, if you remember back to that second case, that woman fit every single one of these criteria. So we decided to look at our experience with sederatective surgery to try and identify better characteristics that we can use to select patients moving forward. So we looked at 566 patients who had surgery between these years and compared them to 110 patients who were treated with their primary tumor in place. Now, MD Anderson is a very surgery-centric institution. We try to be as aggressive as we can with patients. So you can imagine that the patients who didn't have surgery and were treated with medical therapy alone were probably the worst of the worst. And so what we said was, looking at our surgery group, if you didn't survive as long as the worst of the worst, then you probably did not benefit from surgery in the first place. So then we moved forward and tried to identify which factors predicted for survival in the group that had surgery. And what we found was that those patients who had a serum albumin lower than the women of normal, those patients who had an LDH greater than the upper limit of normal, these are blood tests, the presence of liver mets, the presence of symptoms related to metastasis. So, for instance, if you had a met to your hip, if you had hip pain, or if you had a met to your rib, you had rib pain, or you had mets to your lung and you had a cough or coughing up blood, those were all symptoms. If you had evidence of lymph node involvement, either in the retroperitoneum, which is the area around the kidney, or in the chest, those were also predictive of outcome. And if you had locally advanced T-stage, stage 3 or stage 4. And so what we noted was that if you had three or less of those factors, your survival was significantly better than the patients who were treated with medical therapy alone. And we theorized that those patients did do better because of a consequence of surgery. But if you had four or more of those factors, your survival was the same or worse than the medical therapy alone group and you likely did not benefit from surgery. And so moving forward, we're trying to use these criteria to allow us to better select patients, foresight or reductive surgery before receiving systemic targeted therapy. And again, this was a study that we submitted looking at SEER criteria to better select patients and it came up with basically the same factors. So in conclusion, targeted therapy has dramatically improved the outcome for patients with metastatic kidney cancer, but without complete response, surgery is going to remain an integral part of the multidisciplinary approach, either from control of the primary tumor or something we didn't have time to talk about today Show me an agent that generates a reliable complete response and I'll be the first to argue we should re-examine the current paradigm. And as I talked to you earlier about, the pre-surgical approach may have merit, but it still needs further study and validation because it's not clear when it's most appropriate to integrate surgery into the context of systemic therapy. Currently, we're doing surgery first. So thank you very much for your attention.