 See, we'll be a little ambitious today, see how much we can cover. I do have some research support from Estellus Medivation for a kidney cancer clinical trial, but perhaps right now, almost October, the most important disclosure is more athletic, so Red Sox just clinched AL East, so let's go. Learning objectives. I don't think it's been decided yet, we're that good, we're way ahead. So we'll talk about the rationale for cytoreductive surgery, why are we going to do this, how is it being used currently, talk about some of the latest data that's just come out about this, it's been a very eventful 2018 so far, and then look ahead, what can we do next to try to bring this to the next level. So essentially I want to try to, at the end of the talk, have you be able to answer the who, what, when, where, and why of cytoreductive surgery. So as has been mentioned today, a lot of patients unfortunately come in already with advanced disease, disease that's spread outside the kidney. There are several disease types that doing cytoreductive surgery has been shown to be beneficial and fortunately kidney cancer is one of them. So when we talk about cytoreductive nephrectomy, what are we actually saying? So we're talking about doing surgery to remove the kidney, remove the primary tumor in the presence of metastatic or distant disease that is still present. So surgery alone is not curative because we're taking out the big tumor in the kidney but there's still other things around. So the goal is to reduce the overall tumor burden. So again, cytoreduction, cytoreducing, reducing the amount of tumor that's there in the patient. So here are a couple of examples. This is a patient who had a very large kidney mass and this is not a cable thrombus. This is all dense adenopathy that's all matted down. So renal mass, adenopathy, metastasis to the lungs. Here's another case of mass, thrombus all the way up to the heart. Also lesion in the sacrum involving the spine as well as mets to the lungs. And then this is a good size renal mass, lung metastasis, bone metastasis. So again in these cases we were able to do surgery to remove the tumor, able to give radiation therapy to the bone, able to give systemic therapy to treat the rest of the disease, as well as giving bone modifying agents to help bone integrity as well. Here's a patient who had one tumor on the right, one, two tumors in the left, as well as lung disease, gallbladder disease, pancreatic disease, and soft tissue disease. He had actually presented by actually coughing up a piece of tumor. He had had a metastasis to his trachea, and he actually brought in the specimen to his primary care doc. And his primary care doc sent it to the lab, and that's how he was found to have kidney cancer. So for him, because of his bilateral multifocal disease, we did cytoreductive partial nephrectomies. So we didn't take out both kidneys, we just take out the tumors from his kidneys. And then we're able to also remove his gallbladder part of his pancreas and then treat him systemically for the smaller amount of tumor left behind. So cytoreductive surgery is really fascinating to me as a urologist, as a surgeon, because the original trials that showed the benefit of this were run by surgeons, really neat. So this is back in 2001, this is Southwest Oncology Group SWAG. You'll hear other things from ECOG, Eastern Cooperative Oncology Group. So one of the large cooperative groups funded by the NCI. And this was done here in the US, and it was looking at patients who received interferon alpha, so a cytokine. So this is one of the first therapies available for metastatic kidney cancer. Versus patients who had surgery and then interferon. And they found the benefit for patients who had surgery first. So that's great, this started it off. At the same time, we also had a European study, the EORTC. So in Europe, similar idea, and they found the same thing. So surgery plus systemic therapy worked better than surgery alone, great. They then combined forces and did a combined analysis with even more patients in 2004, same thing. They then looked long term, we're now out 2009, eight years later, still benefit surgery plus something else, systemic therapy. So that's great, we've got a pattern going on here. We then had in 2006 really the creation of the targeted therapy era. So now we have investigators who sort of went back and said, well, if it worked with cytokines, what's the effect of doing the same kind of setup with targeted therapies, which we think are better than cytokines? So let's see what happens there. So again, this is patients who received vascular endothelial growth factor, VEGF, these are your suetenibs, your suetens, seraphonibs, things like that. This was a retrospective study and they were looking at the impact of cytoreductive nephrectomy on overall survival. And not surprisingly, they found that the patients who had both surgery and then systemic therapy did better. So again, we're seeing this survival advantage for the patients who underwent cytoreductive nephrectomy in the targeted therapy era. So great, it builds on what we knew before. Interestingly, Dr. Chewary and colleagues then sort of broke it up. And they said, let's see how did patients do when we stratify them by something called performance status? So KPS is looking at performance status, their Karnofsky score. Dr. Karnofsky was a medical oncologist, and they found that patients who had a Karnofsky score greater than 80 did better, where those who had a performance score less than 80 did worse. So essentially, this is looking at how well the patient is doing. So we'll look at that quickly here. There were some questions earlier about what's an ECOG score or a Karnofsky score, you see the ECOG on the left. Karnofsky on the right, okay, so on the left if you're talking ECOG, you're playing golf, you want a low score. If you're talking Karnofsky on the right, you're playing basketball, you want a high score, okay? So they're looking here, saying Karnofsky less than 80. So these are folks who need some assistance in doing sort of their daily activities and things like that. So you're getting a sense that the patients both have metastatic disease, but perhaps there are some differences in terms of how that disease is making them feel or making them perform. So switching gears a little bit, this was a study done in 2016 looking at the National Cancer Database. Again, a large nationally available database that looks at cancer centers that are accredited by the American College of Surgeons Committee on Cancer. So folks that have a good idea about what they're doing with their cancer care. And they again looked at it and saw cytoreductive nephrectomy or no cytoreductive nephrectomy in the era of targeted therapy. Again, seeing about a 10 month advantage to patients who had the surgery. This is again a meta-analysis, so they looked at all these different papers. We've looked at a couple of them so far in the slides. And again, you've got this plot here, everything to the left of this line favors surgery. So again, we're seeing surgery plus systemic therapy after seems to make sense. So in summary, cytoreductive nephrectomy, 2001 to 2017, numerous studies supporting its use from the US, from Europe, looking at combined analyses, long term analyses, looking at interferon, looking at targeted therapies. Great, we seem to be moving along. All wheels are go, we're racing forward, okay? And then we get to 2018, okay, and sort of the wheel fell off the wagon. What happened here? So we had the Carmina study, which you may very well have heard about, certainly generated a lot of buzz in the GU oncology community. And this was a French study, and it was looking at patients who had metastatic disease, and looking at patients who received either su-nitinib, so su-tent alone, or surgery and then su-tent. It was prospective randomized phase three, right? So the best we can get in terms of designing a study, this is what we say leads level one evidence. This is the best we can do. It was, again, metastatic clear cell. So they were focusing all on one histology. Clear cell is the most common kind we'd see. About 75% of patients have that. And again, they were randomized one to one, so 50-50 chance, surgery followed by su-tent or su-tent only. Now, interestingly, they only had intermediate and poor risk. We'll talk about that a little bit more. Survival was their end point, and they enrolled 450 patients from 79 centers across Europe. And unfortunately, we're not seeing the separation that we saw on those prior curves, okay? So overall survival, progression-free survival, what happened? The su-nitinib group alone looked pretty similar to the people who had surgery and then had su-nitinib also. They threw a monkey in our wrench here. I'm not sure what to do with this. So we looked at it a little bit more closely as everyone did in the community to figure out, well, what were perhaps some of the limitations of this study, and what should we learn from it? So in terms of critiques, it was a large study, but it was also underpowered. So when they did their original statistics to figure out what they needed, they needed almost 600 subjects, so 576, and they got 450. It also took eight years at 79 centers, so that averaged out to less than one person per center per year. So as you've heard, the speakers, especially in the surgical talks today, talking a lot about going to a high volume center with a high volume surgeon to get your complex kidney cancer care, this didn't quite live up to that. And again, we have the question about the patient selection, and we'll talk a little bit about the intermediate and poor risk groups. So as you remember back a little bit, if you've ever bought a house, you've spoken to your realtor, and they say location, location, location, well, in the surgical world, it's really selection, selection, selection, right? So the adage is we can teach anyone to operate, we need to teach you how and whom to operate, okay? So making good choices and counseling patients wisely. So this is Tom Starzel, who ran transplant at Pittsburgh for a long time, and supposedly his sort of idea was if you were too sick to walk to the operating room on your own, you were probably too sick to get the operation. So sort of early rubric of idea of stratifying patients by performance status. So here you see what's in, this is in NCCM, this is off their website as of a day ago. You see two different models that we use to describe groups of patients in terms of their risk characteristics. So we have up here, one by Motzer, one by Heng. The Motzer was in the cytokine area, developed in looking at patients from the cytokine era. Heng was developed looking at patients in the targeted therapy era. You see Karnofsky performance status plays into both of them, okay? So it's, again, looking at how the patient is physically doing, as well as looking at laboratory profiles. So is the tumor making them very sick? Is the tumor making multiple different aspects of their blood chemistries and blood work abnormal? And then we can sort of figure out how those patients may do with the therapies we offer them. A month after the Carmina study came out, this paper came out. Again, this is using national cancer database, so not the same level of evidence we would ascribe to a prospective randomized trial. But again, this had thousands and thousands of patients. It looked at patients who had clear cell kidney cancer, at non-clear cell, and at the entire group together. And again, it found an advantage for patients who had surgery and then systemic therapy. It had it in the clear cell cohort only. Had it in the non-clear cell. Not quite as much of a spread here, but I think some of that doesn't necessarily always have to do with the surgery. It also has to do with systemic therapy. Right now, all of our systemic therapies, we fortunately have many, have all been tested and approved for clear cell kidney cancer. We don't have right now an FDA approved therapy for non-clear cell kidney cancer. So when we have patients who have metastatic non-clear cell kidney cancer, we can offer clinical trials or we can take something from the clear cell side of the cabinet and see how that works. Interestingly, they also looked to see about patients who received targeted therapy first and then later went on to surgery. So they looked at a group that had targeted therapy, so systemic therapy before surgery for three months and for six months. And you see that group, the gray line, did very similar to the blue line. So essentially, getting pseudo-reductive surgery, even after some systemic therapy, they still found to be beneficial over just getting systemic therapy alone. Sure. Okay, so again, this is National Cancer Database. So it's a big data set and they look at patients who have been coded as having kidney cancer. And they went and they looked for patients who had gotten systemic targeted therapy for three months or six months and then went on to have surgery and then compared it to patients who just had systemic therapy alone. So the gray is targeted therapy then surgery, blue is initial surgery, and then this is just systemic therapy. So essentially, my take on it is that they're finding that even patients who have had systemic therapy, they can still potentially benefit from again having this cytoreduction, having this debulping or removal of the primary tumor. Okay. Yeah, so yeah, you may very well be one of these data points in here. Yeah. Sure. No, but thank you for your contribution. You show up right here. So, you know, holiday card kind of picture right here. That's great. Yeah. So the questions that still remain for us here. Optimal patient selection, how do we choose and how do we counsel our patients when we see them? So again, we talked about performance status. There's a lot of question about burden of disease. Where is the disease located? Do we want to say we want to do surgery if we can remove 90% of the cancer? If we can remove 70%, if we can remove 50%, as you heard earlier, if it's in brain or bone, we tend to worry more. If it's in pancreas, that tends to do well, same with lung. So those are things that we need to do more work to figure that out. Again, timing of systemic therapy. Again, I think that it's much more common for patients to have surgery and then be able to get to systemic therapy in a reasonable timeframe. I haven't really seen that being a problem in terms of patients recovering and being able to go from there. Again, we have more and more ability to use minimally invasive surgery, so oftentimes we're even doing cytoreductive nephrectomies robotically. Essentially, it's the same morbidity as having a regular nephrectomy and patients are often able to go home in a couple of days. So that's a nice advantage of what we're able to do now. And of course, this mechanism of action. It's great that I've been able to show you a dozen Kaplan-Meier curves, but I can't really tell you in great detail why that is. So is it the idea of this, I talk about soil and seed hypothesis. So the little cancer cells and where they land, is it different if it lands in the liver versus lands in the lung? The idea of tumor heterogeneity. So even though I've got one tumor, there may be sort of different types of tumor cells within it that have different proclivities to going different places or doing different things. Again, this idea of a diaspora hypothesis from Ken Pienta. So again, we don't really understand fully how it works and we need to keep pushing on that to have a better understanding. So to sort of summarize and revisit who, we're talking about patients with metastatic disease overall good performance status who would be up for having a major surgery. What are we trying to do? We're trying to do cytoreductive surgery to reduce the amount of tumor burden as much as possible without getting into things that would cause major complications, disability, disfigurement, prolonged convalescence. Because again, the surgery alone is not curative. We do need to get people to either observation that the volume of disease is low and its growth is slow or systemic therapy. When, usually prior to systemic therapy, I say usually we had that slide we had just been talking about and also I think there are gonna be more and more clinical trials where patients would be offered medicines prior to surgery, especially with the immuno-oncology drugs. There's an idea that they may work very well by still having the big kidney tumor in place to help the body better learn from all the nastiness within that tumor then taking it out and some of the lymph nodes that go with it. Sort of building on Lauren Harshman's prosper trial where patients are getting doses of the immuno-oncology drug before surgery where, as you've heard this and I think this is a limitation of the Carmina study getting your care at high volume centers with high volume surgeons with a team that works regularly together. As you saw in those couple of slides talking to the patients that we've had medical oncology, radiation oncology, urologic oncology surgeons, surgical oncology surgeons, thoracic surgeons, vascular surgeons, neurosurgeons, having that whole team together where we can sit there and make a plan and then execute that plan on day of surgery and it not being an issue. And then why with our goal of improving survival. Future directions, again I think this is an important space for surgeons to remain very active in designing and implementing these next level of trials. Again being able to bring minimally invasive surgery or even just enhanced open surgical and anesthesia techniques as well to enhance recovery and make the operative experience as safe as possible. And then of course new opportunities for cytoreductive nephrectomy trials with systemic therapies. So whether that be perioperative, so getting doses before and after surgery and looking at new combination therapies. Thinking out most solid organ cancers, I think most of them are treated not by a single agent but also often doublet or triplet therapy. So two or three medicines working together and perhaps we're gonna be able to exploit the efficacy and tolerability of some of our immuno-oncology agents to be able to do combination immuno-oncology targeted therapy or immuno-oncology immuno-oncology or even perhaps immuno-oncology TKI. So like ipi-nevo-cabo, a combination where we're hitting the tumor through multiple different pathways simultaneously both before and after surgery. I'd be happy to try to answer any questions.