 As Dr. Wood mentioned, I'm going to be speaking about the role of surgery in the setting of metastatic kidney cancer to include pseudo-reductive nephrectomy, which is removing the kidney, and metastasectomy, which is removing metastatic sites. I have no financial disclosures. So we've already heard today by many of the speakers that metastatic kidney cancer has many challenges. It's not responsive to most traditional toxic chemotherapies. It's not responsive to radiation therapy. The minority respond to cytokine or the traditional immunotherapy. And we have rare complete responses with targeted therapies. We've seen something similar to this with Dr. Gow's presentation on the timeline of kidney cancer therapies from active surgery in the treatment of kidney cancer back in the 1960s to the adoption of immunotherapy in the treatment of patients with advanced and metastatic kidney cancer to the advent of targeted therapy with Seraphanib in 2005. Now on to even some newer targeted therapies and as well as immunotherapies and vaccinations that are coming available. So we know that we have all these medical therapies, the immunotherapies and the targeted therapies. So the surgical therapies that can be incorporated into this are pseudo-reductive nephrectomy and metastasectomy. And really the question of sequence or therapeutic sequence. When do we do these surgical maneuvers in order to try to optimize patients' outcome? And the standard currently would be pseudo-reductive nephrectomy, systemic treatment and possible metastasectomy, but many options exist. So for some of you I wanted to define some of the newcomers here. What is metastatic disease? And I have this discussion with my patients a lot in clinic. Metastatic disease is spread of disease to a site other than the primary site. So in the picture here you can see a tumor in the kidney here. The tumor can spread typically through two directions. One through the blood vessels or hematogena spread. So it travels through the blood and it ends up in another site and then the tumor grows at that other site. Or lymphatic spreads. So here's a depiction of a tumor with tumor spreading to the lymph nodes that are nearby. Sider-reductive nephrectomy is the surgical removal of the kidney in the setting of known metastatic disease. And metastasectomy is removal of a sighted disease that is spread from the primary to another site within the body. And it's still kidney cancer even though it's at another site. And a lot of people make that mistake when they're trying to understand what we're talking about. I also, you've heard a lot of discussions today about different trials, about different studies, about things that without having the background you may not realize why it's so important when we describe these studies. Randomized prospective studies are our gold standard. Those are the clinical trials that we've basically followed similar groups of people over a period of time after an intervention. The intervention may be a new drug, it may be a surgical therapy. Half of the group may get that intervention while the other half gets a standard treatment. And therefore we can actually effectively compare the two and see which is the better outcome. Randomized studies are what make standard of care. And then we look back and see, okay, of those who received the therapy compared to those that did not, what were the outcomes? So as you can imagine, that's open to significant selection bias where if a physician feels that the patient may benefit, obviously they're selecting those patients out. So those are mainly hypothesis-generating studies that help us to develop clinical trials, but they're not things that have already occurred. So patients receive the therapy because their clinician felt that that was an issue that helped us to develop clinical trials, but they're not things that we should be practicing standards off of. And the other thing that came up today a lot is Kaplan-Meier curves. And some people may not even know what the Kaplan-Meier curve is. So I figured I would include this just so you can get a sense of what we keep talking about when we're talking about significant differences in these trials. So Kaplan-Meier curves is simply just a measurement of the fractions of patients alive for a certain amount of time after a treatment. So at time zero, the treatment is applied. You have two populations of patients. They receive different therapies. They may have something in common, but something will be different between the two. And then you look at the outcomes over the period of time, and you say, okay, RMA clearly has more patients alive than RMB. So it makes sense that that therapy may be better. And the reason I tell you that is because I'm going to show you some Kaplan-Meier curves and I want you to see that sometimes these differences are very significant. Meaning a wide split between the curves. And sometimes they're not so significant. And that's what raises the questions that follow. So cytoreductive nephrectomy in the area of immunotherapies. This was when cytoreductive nephrectomy was first evaluated. And this is in two publications from 2001. These were randomized prospective studies. So the gold standard, which looked at immunotherapy with removal of the kidney versus immunotherapy alone. So these are two trials. Both of them, the dotted line on the left side and the solid line on the right side are the arm of the trial that had surgery plus immunotherapy. The bottom lines are the one that had immunotherapy alone. So these are not pre-selected patients. These are randomly assigned patients. And there's a separation of the curves which would indicate that the patients who had the nephrectomy in addition to the immunotherapy had a better outcome. Hence, cytoreductive nephrectomy became part of the standard of care in the treatment of patients with metastatic disease. So in the current era, now with all of the newer systemic therapies since 2005, again, with the advent of seraphonim in 2005 being approved, we see even improved responses both in the kidney and in the metastatic sites with these targeted agents. And the question became, does cytoreductive nephrectomy still benefit or still provide benefit to patients in this era? And then if it does, what sequence of therapy should we undertake? And then can we identify those who actually would benefit most from surgery? So you've seen a lot of these graphs and these depictions and these illustrations of trials. The point is for the Carmina trial, this is asking the question, is nephrectomy or cytoreductive nephrectomy still relevant in the era of targeted therapy, in this case being synitinant? And what all of this really basically says is, does targeted therapy with or without cytoreductive nephrectomy make a difference? And so the groups are randomized and split into those that receive surgery followed by the drug versus the drug alone. The outcomes of this will hopefully be available at some point in the future, but are not available at this time. Another study and from what some of us would believe is probably the more important study is the SIR time trial, which again really just evaluates the sequencing of targeted therapy with cytoreductive nephrectomy. So this looks at all patients receiving nephrectomy, it's whether or not they have the targeted drug or the systemic drug up front or after the surgery is completed. And so the question becomes while these trials are accruing patients and rolling patients and we're analyzing the data and waiting for the outcomes, what do we do? And so this is again now, this is retrospective data. So what has happened already in the past five or seven years in patients in this era and what does that tell us? And these are patients that were selected to undergo nephrectomy in the setting of having not received immunotherapy but being on Sunet Nib as one of the targeted agents and then looking at and comparing those to patients who did not undergo nephrectomy. So the top line of the green line is patients who had the nephrectomy and the blue line is the ones that did not have the nephrectomy. And the green line, patients are living longer in a larger portion of them. But again, selection bias plays into this and it's difficult because are the patients with the blue line not given surgery because they were not offered it at the time or is it because they were not offered it because they were not necessarily candidates for an operation. Similarly, by the paper by Tuari et al. from 2011, we're looking at patients again who had targeted therapy, whether or not they had their kidney taken out so the red line is yes, kidney removed, black line is no, kidney not removed, the red line did better. Patients did better if they had their kidney out. The difficulty here again is the selection bias and as I mentioned, what is the selection bias in this case? These patients, the groups were different, they differed in age, they differed in performance status, they differed in the number of metastatic sites, they differed in the number of calcium levels, which is one of the things we look at when we measure someone's prognostic level. And on the right of the screen, you can see these again, the Kaplan-Meier curves and these are separated out looking just at people with good performance status versus poor performance status. And really they didn't seem to be a benefit to those with poor performance status. So it's difficult to really interpret this but at least it gives us some idea that if patients are surgical candidates it's possible that they'll benefit still from removing the kidney in the setting of targeted therapy. Moving on to metastasectomy. So the difficulty with metastasectomy and this is a conversation I've had with my colleagues is there's no randomized trials looking at metastasectomy. So removing a site of disease, a solitary site of metastases, multiple sites of metastases after the kidney's been taken care of or even with the kidney in situ, there's no randomized trials. So what we have is data on patients that had sites removed and their outcomes and then we're supposed to interpret from that whether or not it's an appropriate therapy. The goal of metastasectomy is to be clinically free of all sites of disease. The benefit, if you can actually remove all sites of disease and in fact patients can be essentially cured of their disease, that would be ideal. But also it allows for a period of time where patients may avoid the need for systemic drugs or systemic therapy. If you can tell someone who thinks they're going to require systemic therapy for the remainder of their life that they can be off drugs for a period of time if they have an operation, it may be something that would be worthwhile. We do know that there's improved survival when all disease is removed compared to when all disease is not removed. We know that survival is related to metastasis so some sites if you've removed tumor do better than others. What we don't really know is the relationship between systemic therapy now and metastasectomy and again sequencing issues of when we should be applying these therapies. These are a number of studies that have been completed again in a retrospective manner looking at the outcome of patients who underwent metastasectomy. The numbers are not meant to overwhelm you. Basically what it says is the resection do better. The question is why do they do better? Looking at specific metastatic sites we know single sites are better than multiple. Resectible is better than unresectible. There are many sites that kidney cancer goes to. Some of the more common ones are ones at least that have been studied are brain, thyroid, lung, liver, bone, retroperitoneum and adrenal. Looking at lung, this is an example of someone with lung metastasis. There are many studies looking at patients specifically in a retrospective manner who have had lung metastases excised. And what we can say is that resection of lung-only metastases, if you can remove all of the metastases those patients do well. 74% cancer-specific survival means they don't die of their disease. Incomplete, the patients that couldn't have all their disease removed had a 19% cancer-specific survival. So far worse than if you can do it. So if you're going to do it and you can do it all, great. If you can't take it all out you may want to reconsider. With liver metastasis over section, the disease-free interval, if they're disease-free for longer than two years it's more likely that they're going to have a better outcome. The absence of lymph nodes in the chest and then a smaller number of metastases at the time of diagnosis. I include liver as a discussion here point just because with lung it makes sense to do it based on the data that we have available. With liver it's questionable and I'll explain why. There are two poorer than patients that don't have liver metastases. This is a small study but it's one of two studies that are available. 17 patients with solitary liver metastases, 11 of them underwent complete resection. Four of them died in the post-operative period. So a perioperative mortality is relatively high for this group. Their mean survival over the course of all of them were 16 months, which is lower than what we've described in some of the others. And then we know the poor outcomes and also those who have impaired function of their liver as a result of their tumor. So now what about again the same question with cytoreductive nephrectomy is what do we do as far as metastasectomy now that we have these better drugs that tumors respond better to? In the immunotherapy era let me just take a step back in the immunotherapy era we do have some data on patients that had immunotherapy followed by metastasectomy and this is an M.D. Anderson study of 38 colleagues, 38 patients received immunotherapy those that did not have progressive disease and no progression at all underwent metastasectomy. Of the ones that ended up having surgery 21% had partial or complete responses we've thrown those words out a lot today too but basically those are the ones that had some response 76% had stable disease so considered non-progression. 76% of these patients could undergo a complete resection 90% of them went on to receive additional systemic therapy after surgery. The median time to progression so the time to when they first had identifiable disease was 1.8 years the median survival was 4.7 years and again back to the receptability 5.6 years if it's completely resected 1.4 years if incompletely resected the predictors of good outcome were having no evidence of disease or any D after surgery or pulmonary metastases the question is asked by Dr. Karam who spoke earlier is what about in the area of targeted therapy what if we do targeted therapy followed by metastasectomy and this is obviously a more recent study because the targeted therapy becoming available in 2004-2005 this was 22 patients again a retrospective evaluation of these patients targeted therapy was given and then their metastatic site was removed lots of different sites were looked at patients 50%, 11 out of the 22 had a recurrence of the ones that recurred the median survival was poor, 10 months and at the end of the follow-up 21 patients were still alive the median survival was 25 months for that entire group and this is I think the key point is that the median time off of therapy so basically a period of free of having to take drug was 13 months his study showed it's feasible to do this but really it needs further study and in a prospective manner is the gold standard to try to show whether or not this is effective and how we can benefit patients most by using it the take home messages for the talk today I think is that surgery is still an important part of the treatment for metastatic kidney cancer the benefits achieved are best in patients that have good performance status good surgical candidates have limited metastatic burden have long disease free intervals have high blood pressure disease patients that need palliation for pain and discomfort and is ideal when complete resection is feasible we need to better identify patients better identify who is going to receive the most benefit from this as you heard about Dr. Woodstock on neo-adjuvant therapies and his attempts to try to select patients that are better candidates for surgical therapy and then clearly we need to study the systemic treatments both targeted in immunotherapy given what we just heard from Dr. Gall I want to say thank you and it was a pleasure to be here