 Good morning everyone. I would like to thank the Kidney Cancer Association and Dr. Wood for inviting me to be here today. It's my pleasure to be here and give this presentation and talk to you all after the presentation as well. So my job today is to talk to you about the role of surgery in patients who already have metastatic disease, whether it's surgery to remove the kidney or to remove the metastatic areas as well. Just to make sure I stay on time. So just to give a few definitions, metastatic kidney cancer means that the tumor has spread outside of the kidney and it's also known as stage four kidney cancer. And when we talk about cytoreductive nephrectomy, we mean removing the kidney in a patient who has metastatic disease. So this is called cytoreductive nephrectomy. And when we talk about metastasectomy, this means removal of a metastasis, which is removal of an area of tumor spread outside of the kidney in a patient who has this issue, which is stage four kidney cancer. So the first part of the talk will be cytoreductive nephrectomy, again, removing the kidney itself and patients with stage four kidney cancer. These are the recommendations from the European Association. As you can see here for stage four, they simply recommend that in selected patients we should do the surgery. As you could tell, this is not very helpful for individual patients. And through the talk, I'll tell you what the nuances are when we try to select patients for this type of an operation. These are from the National Comprehensive Cancer Network guidelines, and this is what they say. So if you have a primary tumor, meaning a kidney tumor that's removable by surgery and an area of metastasis, that's just one area that is removable as well, then this patient should have both the cytoreductive nephrectomy and the metastasectomy. Now they don't have to happen at the same time, but both should be recommended. Now if the patient has a kidney tumor that's removable by surgery, but they have multiple areas of spread, the recommendation in this situation is to do the actual surgery to remove the kidney itself and then give systemic therapy or medications, either by mouth or by vein. And my colleagues from Medical Oncology will discuss that in the second part of the session today. Now if the patient has a tumor that cannot be removed by surgery, or if the patient is not fit enough to undergo an operation, then this patient should in general not have surgery and just receive medical therapy. And this is a more reasonable guideline compared to the European one at this point. So we do have data on cytoreductin nephrectomy in what we call the immunotherapy era. This is the era when our colleagues used to use interferon therapy or interleukin therapy. They are used now, but definitely to a much lesser extent. And on these types of curves, and you'll see a lot of them today, the higher the curve is, which you see it up here, that means a better outcome in general. So here you could see that we're talking about survival and if you do an nephrectomy plus the medical therapy, the survival is better because the curve is higher than just giving medical therapy alone without kidney removal. This was a randomized clinical trial. So this is the best level of evidence that we have. And this was mostly based in the United States, but this was published about 15 years ago. In the same year, a similar study was done in Europe and this is led by our German colleagues. And again, the same concept that you see here. So the higher the curve, the better the outcome. And this is for the study group, which means the patients that had both the surgery and the medical therapy compared to the patients who had just the medical therapy alone. And again, this is a randomized prospective trial. Now when the authors combined the results of both studies, they found the same result basically that if you combine surgery plus therapy, you have a better outcome than just having the therapy alone without surgery. But again, you have to keep in mind that these patients that were entered into these clinical trials had to meet very strict selection criteria. So this is not just any patient that had metastatic disease. These patients were very well selected based on very specific criteria. Now this is a subsequent study and this was retrospective, but they used the same selection criteria. But instead of using interferon therapy, they used interleukin-2 therapy, which is felt to be more aggressive, but also more curative. And as you could see here, this is interferon alone, the lowest curve. So this is the worst outcome. Surgery plus interferon is better, but when you combine surgery plus interleukin, it's the best compared to the other therapies. Now these drugs, as I mentioned earlier, are not given as frequently anymore. So now we live in what people term the targeted therapy era. These are drugs that some of you may have heard of or might have even used. And we don't have any finished clinical trials to tell us what we should do, but we have two ongoing clinical trials. One of them is called carmena and it's based mostly in Europe. And what they're doing is that they're randomizing, meaning they take the patient and by random the patient either receives the surgery nephrectomy, followed by a drug called sunetinib, or they receive just the drug itself without an operation. The primary objective is to compare the survival in both patient groups. And this trial is slowly accruing and it's been accruing for quite some time now. Now a different study also mostly based in Europe called the sur-time trial. As you can see here, both groups received the surgery. One group had surgery followed by the medication. The other group had medication for some time, then surgery and then went back on the medication afterwards. Again, this study is still accruing. So both of these studies, we don't have the results just yet. So in the meantime, what are we supposed to do as doctors? We live in the targeted therapy era, but we don't have any hard evidence based on prospective or large randomized trial to tell us what we should do. So in the meantime, we're basing our practice on mostly retrospective studies. And I'll show you some here. So these are in patients who had nephrectomy. We see that the response rates to therapies appear to be better than patients who did not have nephrectomy. Again, this is retrospective data. Again, going back to the same types of curves, we see that outcomes in general are better in patients who had surgery compared to those who did not have surgery. And you see that for both the progression-free survival and in overall survival as well. These are other studies that I'm just gonna go through. Different studies all showing the same thing, but keep in mind they're all retrospective. Meaning they're not actual clinical trials. Again, the red line is for patients who had surgery. Their survival is better. Yet another study, if they've had surgery, the survival appears to be better. However, we know that universally this doesn't apply. So not every single patient that had received surgery has experienced an improved in survival or an outcome. So how do we really select these patients? And how do we know who to recommend surgery for? So we know there are several factors that in general we look at when we see a patient in clinic. One thing we look at is tumor burden, meaning how much tumor does this patient have? Both in the kidney and also outside of the kidney as well. And this makes sense. The more tumor we can remove with surgery, the better outcome the patient will have. And these are just different cut points that have been published. So if you remove more than 95% of the tumor, it makes sense that the patient will do better than if you remove just 5% or 10% of the tumor. Another factor we look at is the stage of the disease. Now we're talking about patients with stage four kidney cancer, but this particular slide, I'm talking about the stage of the actual tumor itself, meaning how aggressive or how large the tumor is in the kidney itself. And we know for tumors that are very aggressive, that are invading other organs, the outcomes in these patients are not very good if they have metastatic disease already. So in general, we try not to do surgery for this particular group of patients which actually is rare. Now histology meaning what is the type of kidney cancer? As you might know, kidney cancer is not just one disease, there's different types. Clear cell is the most common type. And the other types we can lump them together in one group called non-clear cell histologies. And this makes up about 20% or so of the patients. The data on this are at this point conflicting. There are some studies that say if you do cytoreductive nephrectomy in patients with non-clear cell, the outcomes are better. And there are some studies that say the outcomes are not different. So we are looking at our database currently to revisit this topic to see if we can find out who benefits from this surgery if they have non-clear cell histology. There are also factors that are hospital-based. So this is from a very large database called the national inpatient sample that looked at more than 16,000 patients who had cytoreductive nephrectomy. And they found that outcomes are worse if the patients are older. And I'll visit that in a second. The outcomes are worse if the patients are not healthy, which also makes sense. There are worse in smaller hospitals, meaning that the hospital that does not do this type of surgery very frequently. And obviously the outcomes are worse and survival is worse if the patient has complications after surgery. Now going to age, these are two studies. One of them is from our institution here that found that in general, if patients are over 75 years of age and have cytoreductive nephrectomy, they are at a higher risk of complications and either a higher risk of mortality or dying after surgery. Again, we're talking a small percentage, 5% in patients older than 75, but this number is larger than in those who are less than 75 years of age. So it's important to keep age in mind as well. Now one study that we did hear several years ago to try to identify who might benefit from this type of operation. So we looked at our databases and this is retrospective and try to compare survival in patients who had surgery and in patients who did not have surgery. And again, as we note here, that patients who had surgery did better. However, you have to think that if they did not have surgery here, that means that there is a very good reason why they did not have it. Either they had too much spread outside of the kidney or the patients were too old or too unhealthy to have an operation. And we found that there's these seven factors that can predict who might benefit from surgery. And when we look at these factors together, we found that if the patient has three or less risk factors, they do better than patients who have four or more. Risk factors here. And again, you see the same type of curve. If a patient has three or less of these risk factors, they do better than the other group of patients. And the other group of patients is either patients who did not have surgery. And you can see here that the survival is very similar to those patients who had surgery but had four or more of these risk factors. So in general, if the patient has four or more of these risk factors, we tend not to offer surgery. But again, it's a little bit more complicated even than that. And a similar study was done by a different collaboration from multiple institutions in multiple countries. And they found similar findings. Basically, if you have three or less risk factors, and these are slightly different risk factors than the ones we found, this revival is better than if you have four or more of these risk factors. When we talk about cytoreductinofractomy, it doesn't always have to be through a large open incision. In selected patients, we can offer a laparoscopic cytoreductinofractomy that could offer patients less blood loss, a shorter stay in the hospital, and shorter recovery time, and even quicker start of therapy after the operation. So whenever we can do this operation laparoscopically, we tend to do it this way. But again, this has to be in well-selected patients. And in a very small percentage of patients, we don't even have to remove the entire kidney and we can remove only a portion of the kidney. But this is something that's done very rarely but it can be done in very selected patients. Now, having told you that there are benefits for surgery that surgery is important, there are some arguments against surgery that we should all be aware of. Surgery does have some morbidity, it has some side effects that we always inform the patients about when we do the surgery or before we do the surgery. Again, the only benefit that we know of from large prospective studies comes in the area of immunotherapy, especially with interferon. Sometimes patients can spend a long time recovering from an operation and sometimes the patient can have disease progression after surgery, meaning that the tumor that's outside of the kidney that we did not remove can grow fast sometimes after surgery. Not necessarily because of the surgery itself but that's how the tumor was meant to behave. And in the few weeks after surgery we can't really start the patients on medications because we're afraid of complications from the medications such as wound healing issues and things like that. So we still have some work to do, we need to still better identify patients who might benefit from this type of operation, that's the operation to remove the kidney in stage four conditions. And we also have to find out the correct sequencing whether we should give medications first and then do surgery or whether we should do the surgery and then give medications to treat the cancer. And we're still trying to find ways to improve on the surgical techniques and use minimally invasive surgery whenever it's reasonable to do so to improve the quality of life of patients after an operation. So just take home messages from the first portion of the talk that we're still awaiting the ongoing trials and these trials are being done with targeted therapies. We don't have the results just yet. I think surgery still is an important part of a multidisciplinary plan in patients who have metastatic disease. And surgery is still recommended in patients who are young and patients who have clear cell histology who have good performance status meaning they're behaving as normal as possible. They don't feel very tired, they're not very sick, they're not in bed all day because they're very tired. It's also important to do the surgery or to consider it in patients who have limited disease outside of the kidney and patients who have a limited number of poor risk factors that I mentioned, you know, three or less risk factors and it's preferable to do it in high volume centers just because of the experience of the entire institution, the surgeon, the anesthesiologist and other surgeons that could assist with the operation as well. However, just because a patient does not fall in one of these categories doesn't mean that they are automatically disqualified from having surgery. Again, we have to look at each patient individually and decide with the patient what we think is the best way to proceed. So these are just more recommendations and suggestions but if the patient does not fall in this category, they can still be considered for surgery if appropriate. This is some work that we've done from our institution for further reading if you're interested and I'm gonna move on quickly to the second part and this will be shorter than the first one and this is on metastasectomy. So the first part, we tackled removing the kidney itself and a patient with stage four. Now we're talking about removing the actual spread whether it's in the lung or the liver or other areas and I'll go through this briefly. So there are some challenges in this setting. In patients who have metastatic kidney cancer, we know that most of the kidney cancers are not responsive to traditional chemotherapy. We know that not very responsive to most radiation therapy and the cytokine therapy that's the interferon and the interleukin that I mentioned earlier, most patients do not respond, only a small minority of patients respond to this and with the targeted therapies that are currently being used mostly, there are rare complete responses meaning that it's rare to give this medication and see that all the tumor has disappeared. We see very good responses meaning the tumors are shrinking, they're not growing as fast but it's rare to see that all the tumors disappeared with these types of medications. So there are other options in very well selected patients and you'll hear me say a lot. So not every patient who has spread outside of the kidney is a candidate for surgery to remove that spread. Sometimes there's multiple areas that cannot be removed by surgery. Sometimes technically it's not doable to do the surgery safely and cure the cancer that way but surgery is an option in a group of patients and these are the guidelines, these are similar guidelines that I showed you earlier. This is from the European Association of Urology and basically this is what they recommend that no general recommendations can be made. If we had very specific recommendations you probably don't need to listen to me this morning giving this talk, I'll just show one slide and step down but the reason we're doing this talk is because it's a dialogue and it's not set in stone what we should or should not do for our patients with metastatic disease. So let's talk a little bit about survival in patients who have metastatic disease that have underwent metastasectomy. This is one of the earliest studies from our colleagues from Memorial Sloan Kettering almost 300 patients and this includes patients who had a complete metastasectomy meaning they already had their kidney removed, they had metastasis and these metastases were surgically removed and in this very select group of patients the five year survival was about 44% which is pretty good but again this is a small group of patients and not all the patients who presented to the hospital with metastatic disease and it's important to keep that in mind and what you'll see is a very similar number throughout the studies that I'm gonna show you. This is another study, also five year survival if the patient has had any type of metastasectomy about 49%, this is a much larger study again the survival is about 44% again in those patients who had metastasectomy. This is the total number of patients this is not the number of patients who had metastasectomy and this is one of the most recent studies from Mayo Clinic, almost 900 patients again not all of them had surgery less than 20% had metastasectomy but in those patients who had complete metastasectomy the five year survival was about 45% which is actually quite good and this is the study that I just referenced to you again this is from our colleagues from the Mayo Clinic this was over a 30 year period this is a retrospective study and only 14% of these patients had complete metastasectomy meaning they had complete surgical removal of any disease outside of the kidney and I looked at the impact of surgery based on different factors I'll just show you a few of them here so in patients who had complete surgical resection the survival was about five years compared to those patients who had no complete resection and that's only about one year so we see some separation of the curves again the higher the curve the better the survival is and in patients who had only spread into the lungs if we can remove all that surgically the survival is definitely better than if we cannot do so and this was also true for a disease that's outside of the lungs and you could see also improved survival in patients who had complete surgical removal versus not again keep in mind this is also retrospective and this makes sense if we can remove all the spread outside of the kidney the outcomes are better than if we can remove some of the spread and the outcome is better than if none of the spread has been removed but again keep in mind that if a patient did not have this type of an operation there must have been a good reason why they did not have it again maybe they're old maybe they're not very healthy maybe they have too much spread outside of the kidney that doesn't make sense to go after each area of spread and this is what we call a systematic review so this group of authors looked at multiple manuscripts from the literature and they put those all together in a big table and they studied what are the effects so what they found is that you see here the black box and in all of these studies there seemed to be a trend that metastasectomy can improve survival again all these studies here are retrospective studies none of them are true prospective studies there are specific metastatic sites that usually kidney cancer likes to go to brain is one although it's not very common thyroid is very uncommon lung is the most common one there's also liver, pancreas pancreas typically happens several years after initial diagnosis in majority of cases that do have pancreatic spread but also it's quite uncommon so the majority of spread we see it in the lung, liver and the lymph nodes and then surgery or radiation can be done for these tumor areas for example for brain surgery can be done if necessary can do radiation for the entire brain if there are multiple areas or you can do what we call stereotactic radiotherapy or gamma knife to attack one or two spots in the brain typically if there's a spread into the thyroid gland surgically is done for this for the lung if there is a few spots on the lung that are removable by surgery and that's the only area of spread that's something that can be done as well for a liver in general we try not to do metastasectomies just because in general liver spread is a poor prognostic factor meaning that we don't know for sure that if we do the surgery that we're gonna actually help the patient so we don't really have that much data on removing spread from the liver in patients with metastatic disease of the kidney itself for pancreas we can remove part of the pancreas we can remove the entire pancreas depending on where the tumor is and this is typically done by our colleagues from general surgery and in general the patients do relatively well after this type of surgery again partially because spread to the pancreas happens late after the initial diagnosis we recently published our work on doing surgery for areas of spreading into the adrenal glands into the lymph nodes close to the kidney or in the area where the kidney used to be before and we found that if that's the only area of spread doing surgery can cure up to 40% of patients without any additional therapy so again it doesn't cure 100% of patients but it cures almost half the patients if we select those patients very well of course kidney cancer can also go to the bone and surgery on the bone can be done for different reasons either because the bone has already broken or because the bone is about to break or because the patient is having a lot of pain so either surgery and or radiation therapy can be done in those particular scenarios we can also integrate surgery with systemic therapy meaning either we can give immunotherapy beforehand and this is a manuscript published by our colleagues from medical oncology 38 patients who received immunotherapy and then had metastasectomy and about 76% had complete resection of all their metastatic disease and it took about two years before their disease started to progress which is good and the survival was about five years in this patient group this is another study that was published with targeted therapy and not immune therapy again a small study and these patients received targeted therapy and then had metastasectomy and the survival in this study we found that 21 patients out of the 22 were still alive at about two years after this type of an operation all it shows is it's feasible but this is not the standard of care there are studies also that either give the patients a placebo or a sugar pill after complete removal of metastatic disease or give them a medication you have here different types of medication the one that the clinical trial that's active in the US is this one using a drug that's open so what happens is that a patient has had an infractomy then they develop spread for example into the lung then they have the lung spread removed by surgery and now on CT scan there's no evidence of cancer anywhere so these patients if they go into this trial they either receive a sugar pill or they receive a Pesopinem to try to see if this drug helps but just like Dr. Wood just mentioned in patients without metastatic disease that this type of study did not show any benefit however this has not been done in patients with metastatic disease so it's worthwhile waiting to see what the outcomes will be we definitely need to do more research to see how we time the surgery and patients who present with disease spread when they are diagnosed initially or if they have the cancer spread you know a few years after the initial diagnosis we can use these targeted therapies to test which patient might benefit from metastasectomy we are doing some research on the potential benefits or not of the metastasectomy in patients who have non-clear cell histology and it's interesting to see how many patients might benefit from the surgery but are not being offered the surgery and we don't really have that information again because most of these surgeries are done in specialized centers so take home messages for this portion of the talk on metastasectomy we have to keep in mind from all the data I showed you that there is a selection bias meaning the patients who had metastasectomy had it because probably they were younger healthier, limited disease spread outside of the kidney and probably the patients who did not have the metastasectomy did not have it because they're maybe older too much disease spread or they're not healthy however we still believe that metastasectomy is important in selected patients again these are very similar criteria to the first part of the talk I showed you for cytoreductin diffrectomy if they have good performance status meaning if they're as healthy as possible if they're good surgical candidates if they have limited disease spread outside of the kidney if it took a long time for the cancer to spread that's a good indicator that's better than when a patient presents with spread at the initial diagnosis if we can remove the entire tumor that's a good indicator however we still have to do metastasectomy sometimes for palliative purposes meaning to improve our patient's symptoms such as doing surgery on bone or on brain for example however we know we still need better tools to select our patients appropriately for this type of operation and that's something that's being actively worked on here and other centers as well and we still need to study further the integration of these types of surgeries with systemic therapy to see what's the best sequence for our patients and this is another work from our institution on the role of metastasectomy for further reading if you're interested and thank you very much for your attention this morning