 Thank you very much. I want to thank the organizers for giving me an opportunity to speak to this group. I'm a urologic oncologist, so I'm actually a surgeon and not a medical oncologist. And I was asked today to talk about the evolving landscape of surgery for the treatment of kidney cancer, specifically to talk about localized disease. But I think that because of all the advances with medications and whatnot, the role of surgery has actually evolved for all the different stages of kidney cancer and not just for what, as urologists, we see the localized small renal masses. So I'm going to try to touch upon the whole gamut and talk about how surgery sort of falls into place with everything. So this is a slide just talking about the instance of kidney cancer and how kidney cancer is presenting. It had been steadily rising since the 80s. And in 2013, it appears to have peaked at around 65,000 cases, making it one of the top 10 cancers in both men and women. The reason for this is multifold. Some people believe that there are some factors such as tobacco use, hypertension, obesity, that's leading to the rising instance of kidney cancer. But we can't ignore the fact that although we don't screen for kidney cancer, we image almost everyone for a variety of different things now. If you have back pain, you get an MRI. If you fall and you go to the emergency room, you get a CT scan. And so about two thirds of all the kidney cancers that we see nowadays are found incidentally and are found by accident for a workup for something else. And so because of this, this has dramatically changed how kidney cancer is managed because how we see it and how it presents to us is different. As I mentioned, in 2013, there was about 65,000 cases. It looks like in 2014 this has now peaked and dropped somewhat still the top 10 in both genders and one of the top 10 causes of death in men. And there are over 200,000 kidney cancer survivors in the United States. Now this is a slide demonstrating how the landscape has changed. You can see that over time, more and more kidney cancers present as stage one or confined only to the kidney, which means that more and more cases are being managed just surgically. And this has resulted in a smaller size of presentation and has changed how we manage the cases. And this is just from the National Cancer Registry demonstrating that stage one kidney cancers are on the rise. And this is data from Memorial when I was a fellow looking at the different stages of kidney cancer. And again, stage one is the predominant stage. And so most kidney tumors now present at a very small size, less than four centimeters, making it T1A. And this is looking at the Sierra Cancer Registry. And again, you can see that the biggest spike, although the spike is up in all different size categories, is between the zero to two and zero to four size. And what we've learned over time is that these small kidney cancers are actually a unique subset of these small renal masses. And some of them are benign. And some of them actually have a more indolent histologic subtype. And we heard about people with chromophobe, people with papillary, or at least papillary type one. And these don't necessarily need to be managed with radical surgery, which is what the treatment has been for many, many years. But unfortunately, despite this, up to a third of patients will present with locally advanced or metastatic disease when they first present. So I don't think I need to educate this crowd about this, but this is sort of one of the staging systems. Stage one is confined to the kidney, less than seven centimeters. Stage two, still limited to the kidney, no lymph node metastases, but greater than seven centimeters. Stage three would be what we consider locally advanced, maybe a lymph node nearby or involvement of the vena cava or some surrounding structure. And then stage four would be metastatic disease or advanced disease. The reason I show this is because I want to break down the surgical treatments based on sort of the stage of presentation. So what has driven the surgical management to change is the fact that these are presenting in a different fashion than they did 50 years ago when people started doing nephrectomies and that we have a better understanding of the different histologic subtypes and also what the natural history of these tumors are like. We've also become aware that the kidneys are a very important organ in your body. And although God gave us two kidneys and you can survive on one kidney, there are some things that could happen if excess kidney is removed or kidney tissues unnecessarily removed. And this can have an impact on some of the outcomes that we don't think are necessarily associated with kidney cancer, such as cardiovascular effects and whatnot. So the understanding of all these things has sort of driven our field to change how we treat kidney cancer, particularly in the early stage. So in terms of treatment, surgical treatment, this is still the primary treatment for almost all stages of kidney cancer. And that is for stages one through three, it's done with curative intent. For stage four or for patients with advanced disease, it may be palliative to decrease pain to stop bleeding. But it also has been shown to have a therapeutic benefit even in patients with advanced disease. And this is just one of my patients with a localized kidney tumor and one that nowadays would be treated with a very different type of operation than would have been treated 50 years ago. So for patients with kidney cancer only confined to the kidney, you really break it down into those with localized disease or perhaps low risk disease and those who have localized disease, but high risk factors, meaning risk factors that would suggest that they're going to recur. And up to 50% of patients with localized disease who are high risk may end up having recurrences later on. And then I'll also talk about how with the development of these new drugs, where surgery falls into place for locally or advanced metastatic disease. This is a photograph of a case I'm actually going to be doing this Tuesday. And this patient presented, you can see with only organ confined disease, but he has a tumor thrombus that's growing up the inferior vena cava up to the liver. And so this is clearly a high risk but locally advanced tumor. This patient does not have metastatic disease and therefore surgery is going to be his primary treatment. This is another case, however, where despite the fact that the tumor in the kidney may not be very large, you can see that there's a significant amount of adenopathy or spread to the original lymph nodes making this patient a advanced or metastatic patient. So these are the primary treatment options and many of you know about this or have actually had this done and that would be radical nephrectomy, partial nephrectomy or nephron sparing surgery. And this includes both removing the affected portion of the kidney or destroying that part of the kidney with a blade of techniques. And I just want to briefly talk about the concept of watching these or observing these. This is something that's become apparent to us as urologists or urologic surgeons that perhaps not every single kidney tumor needs to be removed. In terms of radical nephrectomy, this dates all the way back to the 60s. The concept back then was to take everything out in the area. The adrenal gland came out. And remember, these patients presented not because they had a CAT scan that showed anything. These patients presented because they had blood in their urine. They had a big palpable mass in their abdomen or they had a lot of pain. So many patients presented very, very far down the road. Survival rates were very good at that time, 48%, which was unheard of for something like kidney cancer, and it had a low mortality rate. And this really set the standard for the next 50 years on how we would treat kidney cancer, which was to take everything out. But just like all the other cancers, this did evolve over time. In terms of removing the kidney, we went from making big incisions where we would remove the rib and take out the whole kidney. And then we started using minimally invasive techniques through what we call laparoscopic or keyhole surgery. And that was becoming popular in the 2000s. Nowadays, we still do laparoscopic or keyhole surgery. Many of us now utilize a machine called the robot. It's still just another form of laparoscopic surgery, but it does allow us to be more facile inside the body. The majority of radical nephrectomies nowadays are performed laparoscopically because it is significantly less morbid for the patient. The cosmos is better, the significantly less pain. If you know anyone who had the big old fashioned saver sword incision, they often develop a hernia and it can be disfiguring. So nowadays, we really have shifted towards minimally invasive surgery. We still do open surgery. For instance, the case with the vena cable thrombus, that has to be done open. We also do it for patients who have locally advanced disease or patients who have significant lymph node involvement. But we've really moved on from the concept of taking out everything to just taking out what needs to be removed. And this is something that's seen in breast cancer and sarcoma. A lot of tumors don't require that you remove the whole kidney. And this really began with the concept of learning how to do stone surgery back in the 60s. And we learned that you could successfully cut out a piece of the kidney and repair the kidney and the kidney would still work. But there was a lot of concern early on that by doing this, you were going to leave tumor behind that they were going to develop new tumors. And perhaps this wasn't a safe operation. This is an example of a kidney tumor that I removed. And this is with a partial nephrectomy done robotically or laparoscopically. And nowadays, we're using three dimensional imaging on a 3d printer, we're taking the CT or the MRI and making a model of it so that we can use it as a guide intraoperatively. Over the next 20 years, the safety of this approach of organ conservation or sparing the rest of the kidney was controversial. And people really did it. If you had to do it, you only had one kidney. You had multiple tumors in one kidney. Or if you had kidney tumors in both kidneys, then people were starting to do partial nephrectomy. But it was still something that was considered compulsory and non-elective. And it wasn't until around the 2000s that we began understanding that, you know what, there are other things that we have to worry about when we operate on the kidney, not just the cancer. And one of the things that we looked at, that we published in Lancet Oncology in 2006 was what's the impact of removing the kidney on someone's kidney function? And you can see here that we demonstrated that those who had a partial nephrectomy had a significantly lower risk of developing chronic kidney disease than those who had radical nephrectomy. And it was this awareness that you were actually potentially doing harm if you removed the whole kidney unnecessarily that drove many of us to start doing partial nephrectomies. We then followed this up by looking at outcome data from the serocancer registry, looking at the development of cardiovascular events, such as stroke or heart attack or CHF. And you can see that those who had partial nephrectomy did better. And then we also looked at overall survival. And those who had partial nephrectomy seemed to have a better overall survival. And this you have to keep in mind is overall survival, not cancer specific survival. So over time, we've recognized that if the cancer treatment success is the same, then we should also try to maximize the impact of the cancer surgery on the rest of the patient's health. So over the last decade or so, partial nephrectomy really has become the standard treatment for patients with small localized tumors. And when I say small, I say about four centimeters or less. This does have its own set of risks and complications. The kidney is a very bloody organ. And so we have to clamp the kidney when we operate on it, cut out the tumor and then sew it together. Because of time, I did not include any videos. But if anyone wants to see what that looks like when we do that, I'm happy to show it to anyone who wants to look at it. But this is associated with its own set of risks. The kidney can bleed. You can develop a urine leak because the job of the kidney is to make urine. And you can also injure perhaps the ureter or any surrounding structures. So it does have a higher complication rate than doing a radical nephrectomy. But many of us believe that the benefits of doing a partial nephrectomy outweigh what the risks are of doing partial nephrectomy. This can be done through an open incision or it can be done minimally and basively through small holes. And so you can see how this has really dramatically changed how we treat kidney tumors. At NYU, for instance, from 2005 up to 2013, you can see that for small kidney or 2011, 90% of all the kidney tumors we treat four centimeters or less are treated with partial nephrectomy. So we really have abandoned the concept of taking out the whole kidney unless it's necessary. This has been somewhat slower as time has gone on around the general population, but this is also catching up as well. And so many of us believe that for four centimeter tumors and certain tumors up to seven centimeters, that partial nephrectomy, if you can do it electively is the treatment of choice. Another way of perhaps treating the kidney tumor was to destroy it or ablate it. You can freeze it, you can stick a needle in it, you can cook it, you can microwave it. We're very good at destroying things. But the issue is how safe is it? And how is it better or worse than physically removing it? And one of the things, as I mentioned, is doing a partial nephrectomy is associated with complications. And not every patient who shows up with the kidney tumor is fit enough or healthy enough to undergo surgery. So the concept of sticking a needle in it, and treating just that part of the kidney or freezing just that part of the kidney is becoming increasingly popular. One of the issues with this, however, is that it can only be done in patients who have kidney tumors generally three centimeters or less. And the oncologic efficacy, meaning how successful it isn't completely treating the tumor is slightly less than having it removed. But for a patient who was very sick, who could not tolerate general anesthesia, who cannot tolerate surgery, this is a very attractive option. You can see here that disease free survival rate for small tumors is around 85 to 90%, which is comparable to the 95% that we see when you remove the tumor physically is limited to four centimeters or less. And like partial nephrectomy, it does have kidney functional benefits, you can see here in this study, that using ablation actually preserves kidney function better than perhaps partial nephrectomy, and certainly better than removing the entire kidney. And I just want to briefly talk about active surveillance. So many of you may know about the story with prostate cancer, how prostate cancer, some prostate cancers don't need to be treated and how it's a disease that that's slow growing. Well, not all kidney tumors are like that. But when we see these small kidney tumors, many can be treated like that, meaning that it's at such a small size and stage, and perhaps it's actually benign or of a lower malignant or indolent histologic subtype. There's a strategy of perhaps just watching it, just getting scans on it and preventing the patient from undergoing any sort of treatment. And this is a calculated risk, you're talking about how risky is it to have this in your body versus how risky is it for you to have treatment. From looking at studies where we just watch these these do grow slowly, about 0.3 centimeters a year. And really, if we wait till they get to three centimeters or greater, the risk of metastasizing is very low. So this is a good way of perhaps treating patients who have a lot of comorbid conditions or who otherwise would not be able to tolerate the surgery. We looked at this and we're publishing this in JAMA surgery this year. And you can see here that in terms of cancer specific survival, for select patients who have small kidney tumors, whether you remove the whole kidney part of the kidney or just watched it, they're extremely comparable. In terms of overall survival, those who watched it did the worst, but they weren't dying of kidney cancer. And this is probably because of patient selection, they were very sick, and they were not good candidates for surgery. That they ended up not having no treatment for their kidney cancer. So how has this evolved? And what are the current treatment trends? So again, this is from the article that we're publishing this year, you can see the use of radical nephrectomy taking out the entire kidney is going down. The use of partial nephrectomy is on its way up. The use of ablation is also on its way up. And at this time, many of us still don't feel comfortable watching it. And so right now, the surveillance or observation of small kidney tumors is low. But I think many clinicians would agree that perhaps this is a very reasonable way of treating patients who show up with a little tiny one or two centimeter kidney tumor, because they fell or broke their hip or whatnot. So there's certainly more interest in looking at this as time goes on. This is just a demonstration or a slide looking at the use of laparoscopic or minimally invasive surgery. And the bottom line is again, radical nephrectomy on its way down, big open incisions on its way down, the use of keyhole surgery laparoscopic surgery on the way up. So for localized kidney tumor, surgery really is the only treatment. It's highly curative. And many patients don't go on to recur or need any additional treatment. Now, even if you have a localized tumor, but you're considered intermediate or high risk, the possibility of it returning is quite high. So surgery may or may not be the only necessary treatment. With all the new medications that we've heard about for metastatic disease, the targeted therapies and whatnot, there's been a lot of interest in looking at patients who have high risk localized disease, and perhaps giving them some treatment after they've had their surgery. The use in the immunotherapy trials of adjuvant treatment really had no demonstrable benefit. And we're beginning to look at and we're beginning to find out now, whether or not giving a targeted therapy after kidney cancer surgery has some benefit. This slide, Dr. Dutcher is kind enough to give me and it's really advocating the use of enrolling people into clinical trials. And these clinical trials can enroll patients either before or after their surgery. And this allows us to collect their tissue and use it to examine what the molecular profile of these cancers are to also look at what types of tumors are metastasizing. We heard this morning a little bit about how clear cell is the classic kidney tumor that metastasizes. But I think as we look at the results of some of these trials, we're beginning to realize that there are a lot of people who are more than what we thought who have chromophobic papillary that are metastasizing. So it's very important that we do, if we can, participate in these clinical trials. And it also gives us an opportunity to figure out, well, if these people respond, what was it about them that led to this response? There are no published trials to date on adjuvant data. But there are a couple of trials that are either closed or closed to accrual. And these are just some of them using seraphonib, for instance, another one using syndinib and seraphonib, which apparently the results Dr. Dutry said are going to be released this year at GUASCA. There's one with posoponib as well. And there's another one with an mTOR inhibitor called Evers, which is actively accruing. And so many of you are possibly being treated or being followed at centers that are accruing people in these clinical trials. So in terms of localized disease, surgery has evolved. It's a shift towards minimally invasive surgery. It's a shift toward renal preservation. We can even perhaps watch some of these. And now we're also looking at adding medication on after surgery. So I want to just finally talk about the role of surgery in people with advanced disease, metastatic disease. And during the cytokine era, surgery was a very important part of it. It was demonstrated that if you had your kidney removed, even though you had disease elsewhere, this did improve survival. And this is a classic study published in New England Journal by Flanagan demonstrating that the role of cytoreductive nephrectomy in patients during the cytokine era. Now that we've moved on to targeted therapies in addition to cytokines, the question is, is removing the kidney still necessary? Does it still help if we have so many of these good drugs out there? And we don't know the answer to this yet. So at this time, because we don't know the answer, many of us still borrow or think of the results that we had back in the cytokine era saying, well, perhaps if we can, let's take out the kidney. And this certainly is reasonable for patients who are having a lot of pain or bleeding from their kidney. And it's also expanded to perhaps removing any metastatic lesions as well as this may improve outcomes even in the era of targeted therapies. One of the reasons why we think that this is probably beneficial is when you look at many of the landmark trials using these new targeted therapies, 90% or so of these patients all had their kidney removed in these trials. So it's still an integral part of how we treat patients with metastatic disease or advanced disease. And so it should not be forgotten yet unless we prove that removing the kidney does not help the patient. As I mentioned, there is no good level one data. This is a study looking at cytoreductive nephrectomy or removing the kidney in the setting of metastatic disease in patients with targeted therapy. And there was an improvement in survival if they had their kidney removed. This improvement really was best in patients who had a good performance status who were considered healthy enough to have the surgery. If you operate on someone who is in bad shape, who is not doing well, who's unlikely to survive the surgery, it's unlikely to have any benefit for the patient. So we have to be very careful about selecting the appropriate patient to undergo surgery if they show up with widely metastatic disease. And so for us, good candidates are those who only have lung metastases, who have good prognostic features or people who are really suffering from having the tumor in their kidney. Bad candidates or candidates that we would turn away and say it's probably best not to operate on you would be those who had what we call a poor performance status or those if you use a risk stratification system are considered poor risk. And when you look at the NCCN guidelines, cytoreductrinifrectomy is still an important part of treating patients with metastatic disease if it's receptable and if they can tolerate it. There are a couple of trials out there looking at or investigating should we just take out the kidney and then give a targeted therapy or should we just put the patient on targeted therapy. And these are either open to accrual right now. Once the carmena trial, once the sur-time trial. And then there's a plug for this trial, which is the ADAPT trial, which is not using a targeted therapy, but actually using a type of immunotherapy where patients own dendritic cells are harvested, their tumors harvested at the time of kidney cancer surgery. These dendritic cells are then sensitized or programmed to attack their own kidney tumor and then given back to the patient. And many of us work at centers where this trial is open right now and you can see here that this is either randomized to just getting the standard targeted therapy versus getting this dendritic therapy along with targeted therapy. And finally, if these targeted therapies are so good in metastatic disease or effective in metastatic disease, what if we decide to give it first before we take out the kidney or before we take out the metastatic lesion. And so this is helpful in making patients who were previously unresectable, receptable, those who are going to lose their entire kidney to perhaps just losing part of their kidney. And it also allows us to have a treatment first and then to go back and do what we call consolidative surgery to remove any remaining lesions or cancers that are still there even after the treatment. In addition, it's almost like a litmus test. If you give these targeted therapies ahead of time and you respond, perhaps you're going to then do well with surgery. And if you don't respond or if you progress, then perhaps you would not be a good candidate for surgery. So there's a lot of interest in using these targeted therapies prior to site or reductive and effective. I have to say that the response rates that we see are not terribly impressive, but there are certainly cases out there where giving it prior to surgery can result in dramatic downstaging. And this is not only of the primary tumor but the metastatic lesion, which can allow the surgeon then to go back after the treatment and remove whatever residual disease is left. There are some theoretical disadvantages. This may compromise the ability to undergo surgery. If the patient does poorly during the treatment, it also can make the surgery more complicated or increase the risk of complications during the surgery. But the limited data that we have suggests that this is not really such a big deal. I had mentioned that perhaps giving it up front may be a good litmus test. And you can see that in some studies where they gave it up front, those who had some sort of treatment response early when they went on to get their kidney taken out did the best. So giving it up front, looking for a response may be one way of sort of weeding out who should have their kidney removed and who should not. Another study looking at phase 2 data of 66 patients who got, again, a type of targeted therapy up front, they found that for intermediate risk patients who responded they did the best as opposed to patients who had poor risk or who were really not good candidates for surgery to begin with or had poor risk factors that these patients did not do well even after they got treatment up front and surgery. So in terms of advanced kidney cancer, the surgical treatments are still the same, but how we can incorporate surgery with these medications is evolving. And targeted therapies are definitely an integral part of the treatment for advanced for metastatic kidney cancer and how we as surgeons can participate in the treatment of these patients' care remains to be seen. At this time, however, cytoreductin refractomy is still considered a treatment standard for good surgical candidates. Up front treatment may have some advantages, such as down staging and weeding out those who are going to benefit from surgery. And again, we have to stress the importance of enrolling in these clinical trials if you're being treated at a center that offers these trials. So in conclusion, there have been significant changes in the past 20 years about how kidney cancers present. And surgery still remains a treatment option across all stages of kidney cancer. For localized kidney cancer, the shift is towards preserving renal function and conservative management for small kidney cancers. For advanced kidney cancers, we are trying to still figure out what the best time to have surgery is and how it falls into place now with all these brand new targeted therapies. Thank you very much.