 So, without further ado, let's get started. Our first speaker is Dr. Jose Caram, and Jose is going to talk about the management of locally recurrent kidney cancer after definitive treatment. Jose? Good morning. I would like to thank you all for being here this early in the morning, and I would like to thank the Kidney Cancer Association and Dr. Wood for the invitation to speak to you today. So, the task I've been assigned is to talk about the management of locally recurrent kidney cancer after definitive treatment. So, this is talking about patients who already received treatment, had the recurrence in the area of the kidney, and now what are we going to do for our patients? Just to go over some definitions, definitive treatment means that the treatment was done with an aim to cure. So, this is a patient who comes to clinic, has a kidney tumor, and the options were given, and the patient is curable, and that is considered to be definitive treatment. Different ways to do this. We can do ablation therapy. You might have heard of radiofrequency ablation, for example, or cryoablation. This is one way to result in definitive treatment or cure. The more standard way to do it is to do surgery, which could be not either open surgery through an incision, could be done laparoscopically through small incisions or tiny holes, or robotically with the assistance of the robot. And that could be either a partial nephrectomy, which means removing a portion of the kidney that contains the tumor, or a radical nephrectomy, which is removal of the whole kidney that contains the tumor. And one of my colleagues, Dr. Matin, will be talking to you about these options in more detail, so I will not dwell on these any longer. Now, the definition of a local recurrence, again, it's the recurrence of a tumor that has already been treated. So, these are all tumors that I'm going to talk about today that already had treatment in the past, and now we're doing it the second time around. And the location for a local recurrence is an area of the body called retroperitoneum. And this is an area where the kidney lives. It's basically deep in the back area, and it's surrounded typically by intestines and by liver, for example, on the right side, by the pancreas and the spleen, as well as intestines on the left side. So it's a tricky area to go back to for another surgery because of the scarring that results from the initial operation or from the initial ablation treatment. And that could include either the kidney itself, and this is in patients who already had a partial nephrectomy or ablation, so the kidney's still there. Now it has another tumor, and we have to go back and do something to that recurrent tumor. Or it could be where the kidney was, and that's called renal fossa. That's basically the area that's between the muscle of the back and the intestines, and sometimes tumors can recur there. Or it could be the adrenal gland. Most of the times we leave the adrenal gland in place if it's not involved with a tumor, so tumor can recur in that adrenal gland. And the other place where local recurrence could take place is the lymph nodes. We don't always remove the lymph nodes. We only remove them typically in patients who have very high risk disease, very large tumors. So tumor can recur in those lymph node areas on the same side of the tumor. So the question is really, how often does a local recurrence happen? Are we talking about a phenomenon that happens in half the patients and 5% of the patients? So it's very variable, and it depends on how we treated the patient in the first place. So with local therapy, ablation therapy, the one I mentioned, the cryoablation or the radiofrequency ablation, it should happen less than 10% of the time. Now, it depends on what studies you read. You might read that the recurrence rate after local therapy with ablation is about 20% or 25%. And this is something that used to happen in the past when people initially started using the ablation therapy and weren't as familiar with it, weren't clear about the indications. So if you treat a large tumor with ablation therapy, the chances of recurrence are higher. So now we know we try to limit the ablation therapy to smaller tumors. And with that maneuver, we have a higher success rate. So if you treat a tumor that's less than two or three centimeters with ablation, the recurrence rate should really be less than 5%. So this is all about patient selection. Now, the local recurrence rate after a partial nephrectomy should be around 5%, and I'll discuss this in detail a bit further. And with radical nephrectomy, the recurrence rate should be less than 3%, because the whole kidney's already been removed. So the chances of recurrences are low. And I'll talk in greater detail about our experience with local recurrences after radical nephrectomy. So how do we find the local recurrence? There's two broad categories on how we do find it. One of them is routine imaging. So basically, the patient has surgery or ablation. We tell the patient, come back in six months with CAT scans or MRIs, and we see something there. That's one way to find it. This is typically in a patient who has no symptoms, and we only found it because we're doing routine imaging as dictated by our guidelines. The other way to find it is if there are symptoms after treatment. And typically, this happens later. So you don't see this three months or six months or a year after surgery. This typically happens years after surgery when the patient probably is not getting any more CAT scans or MRIs, and now the patient's complaining of either a pain in the abdomen or the back area of bleeding in the urine, for example, of being tired all the time, which is not something that the patient had before, of losing weight without any explanation. So the patient is not trying to actively lose weight or feeling a mass in the abdomen or on the side. So now that we found the local recurrence, what should we do next? So the CT scan has been done. It showed there is, let's say, a 4 centimeter mass where the kidney was. Now what to do? So the first thing to do is to make sure there isn't any cancer anywhere else. So we don't just do CAT scan of the abdomen and then just go rush for surgery. So we have to make sure that the chest area is clear. So we do either a chest x-ray or a CT of the chest to make sure there isn't any metastasis in the lungs, for example. We have to very carefully review the CAT scan or the MRI of the abdomen because we're not only interested in the local recurrence. We also have to make sure the other organs in the abdomen are free of disease or if they have disease, we need to know that. So we have to check the liver very carefully. We have to check the pancreas very carefully. We have to look at the adrenal gland on either side if the adrenal gland is still there. And we have to check the lymph nodes as well. And during those CAT scans, we can also see the bones of the spine. So all of these organs have to be checked carefully, not just the area of the local recurrence. If indicated, we need to do an MRI of the brain. And that's typically if the patient has a new headache, if the patient's had a seizure recently without a prior history of seizures or if there is any visual changes. And also, we can get a bone scan if indicated if one of the blood tests called alkaline phosphatase is high. That might tell us we need to get a bone scan. Or if the patient has new bone pain that wasn't present before, that should also tell us probably this patient needs to get a bone scan as well. And this will conclude our what we call a metastatic workup. So basically, we're looking at the area of interest, but also making sure there are no cancers anywhere else in the body, because that factors in into our decision how we're going to treat the patient. Sometimes what we think is the local recurrence is very small, let's say a 1 centimeter area. Sometimes it's a good idea to wait a little bit, especially if that local recurrence was discovered very soon after surgery. So let's say surgery was done today. Three months the CAT scan shows a one centimeter spot. It's probably a good idea to wait another two or three months and do the imaging again, because we don't want to go back very soon after the first surgery to remove that one centimeter mass and then do a CAT scan two months later and find there's another spot somewhere else. So sometimes it's good to wait a short time to make sure that that's the only spot that's present that needs our attention. And waiting two or three months in general doesn't really affect the overall survival because we're carefully monitoring our patients in that fashion and that might spare the patient another operation, for example. Sometimes we need to do a biopsy. Sometimes the lesion or the recurrence on the CAT scan or MRI is very obviously a cancer, but sometimes it's not. It could be just some scar tissue. It could be a tiny piece of spleen, for example, that some patients have as a normal variation. So sometimes we do a biopsy to make sure what this is, especially if the way it looks on the CT scan is not clearly a recurrence of kidney cancer. So these are all things we think about when we see a patient that has a local recurrence. So at this point, we've finished the metastatic workup. We kind of have a better idea of what the patient has. What are the scenarios that face the patient at this point? So the best case scenario is just to have a local recurrence only. So just the recurrence in the area of the kidney or the kidney was or where the remaining kidney is. The other scenario is that sometimes we see a local recurrence, but also in the presence of distant recurrence, which is metastatic disease. This could be anywhere from lung or liver or bone among other places. So the treatment options for our patients with local recurrence can be anything from observation initially, especially if the local recurrence is very small and limited to one area. It could be ablation therapy and I'll touch up upon that in a minute. It could be surgical resection, which is the most definitive way to do it, or it could be systemic therapy. And this is especially true in patients who have local recurrence, but also have metastatic disease. So how do we make up a decision? How do we decide what is the thought process? So there are different factors. It's not simple usually. So we have to think about the patient factors first. So how old is the patient? If the patient is 80, it's different than when the patient is 40. Also, we have to think about the performance status. A patient who's 80 who does everything normally, he's very active or she's very active, they work, they are physically active. This is very important to know. It's different from a patient who's 80 years old, who's, for example, wheelchair bound or cannot move very well. We have to also keep in mind the kidney function. If the patient has both kidneys, if one kidney function is good, and the patient has local recurrence on one kidney, we might decide to remove the whole kidney instead of doing a repeat partial nephrectomy, for example. We have to think about the comorbidities. So if the patient has multiple heart attacks, seizures, strokes, is on two blood thinners, it's different than a patient who is healthy otherwise. So we have to keep all these factors in mind. If the patient has other cancers, and this is something we see in our center, so sometimes our patients have kidney cancer, but also have other cancers that could be more aggressive. So sometimes we have to prioritize the treatment. And also we have to talk to the patient and see what he or she wants from the treatment. What are their expectations? Sometimes patients tell us, well, I really want quality of life if I'm not having symptoms and the tumor is small. I just want to watch it for some time. I don't want you to do surgery on me again, and then potentially have complications. So we always have to see what the patient wants from our treatment and what the patient expectations are before we decide on how to treat the patient. We also have to keep tumor factors in mind. How big is the tumor? So if the tumor is one centimeter, we can afford to wait a bit on the tumor before going for treatment, but if the tumor is already 10 centimeters, we don't really have that much time to wait any longer. Also depends on the tumor location, and if we can do ablation or surgery, so that also factors into our decision. If the patient is being observed for the local recurrence, that gives us different data points so we can see how fast the tumor is growing. If there's one tiny spot of recurrence that's one centimeter, we do a scan again in three months, it's 1.1 centimeter, we can easily decide to keep watching it for another three months, and just basically every three months we evaluate all the options in front of us. And also the biopsy result certainly is important if we do do a biopsy. So just to go over the outline of the different treatment options, I'm gonna talk initially about recurrence after ablation therapy, then talk about recurrence after partial nephrectomy, and finally recurrence after radical nephrectomy. So recurrence after ablation therapy, and these are again, this is a patient who had cryoablation or radiofrequency ablation, and these are patients after the ablation we do routine imaging, typically every six months with a CAT scan or an MRI, and the risk of recurrence should be less than five or 10% if we do choose the patient and the tumor very carefully. And the options for our patients who have a local recurrence after ablation could be anywhere from observation, just keep an eye on it, could be repeat ablation, or it could be a surgery. And I'll go over quickly three different series, and these are the three largest series, but you'll see that the numbers are actually quite small, which is good. This is from our colleagues from the Cleveland Clinic. They looked over their studies about nine years. They had 10 patients who had the local recurrence after ablation therapy that had surgery. Four had radiofrequency and six had cryoablation. There were more patients who had recurrence, but these are the ones who were treated with surgery. Two of the patients had a partial nephrectomy. Again, this is partial nephrectomy after initial ablation therapy that failed. Seven patients needed a radical nephrectomy, which means completely remove the kidney that had the cryoablation done, and one patient had abort surgery because that one patient basically had one kidney. There was a recurrence in that kidney, and this is where what I was talking earlier about the patient wishes and expectations is very important. So this patient told his doctors that if you go to surgery, try to remove the tumor, but if you find that the tumor is not removable, I don't want my whole kidney to be removed because I don't want to be on dialysis. So that's why it's very important to talk to the patient and see what the patient wants. On the other hand, we've had the same conversation with other patients that say, I don't care if I'm on dialysis or not, I want the cancer to be removed, so that way you know during surgery what's the best way to proceed, and that's the best time to know this information is before surgery when we're seeing the patient in clinic and see what the patient wants to do. The tumor size was relatively small, about three and a half centimeters in the series, and the operative time is about four hours, which tells you how complicated these surgeries are because of the scar tissue from the initial ablation therapy. Blood loss is about 700 cc's in this series. This is the second series from the National Cancer Institute. Again, the same scenario took over about six or seven years. These are 13 patients who had VHL. All patients had radiofrequency ablation, and all these patients had partial nephrectomies. And the average number of tumors removed and this patient population was about seven tumors, which is not unusual because the patients with VHL syndrome have a tendency to have multifocal or multiple tumors in the kidneys, and this is typical of what is seen in this patient population. Average operating time was about eight hours in this cohort, and again, this tells you how difficult these surgeries are, especially after ablation and especially after removing many tumors from the patient. Blood loss is quite large, is about 1.5 liters in this series. This is our experience, which we published last year, about seven years worth of data collection. We had 14 patients, 10 of those had radiofrequency ablation, and four of those patients had cryoblation. Surgery was done on average about two years after the ablation therapy was done, which tells you it's very important after ablation to keep doing imaging to make sure that we don't have a recurrence, because if we do have a recurrence, we can deal with it and we can treat it. 11 of those patients had a partial nephrectomy, and three patients had radical nephrectomy. The patients that had a radical nephrectomy included patients who already had a tumor and gone to the vein of the kidney. One of them, we were able to do a partial, but two of them, we had to do a radical nephrectomy because of the extent of the tumor in the vein. And one patient already was on dialysis, so radical nephrectomy was done. Average age at surgery was 65 years. Surgical time was about three and a half hours, which is not unusual for these repeat cases. Blood loss was about 200 to 300 cc's, and the tumor size was about three centimeters. We had four major complications, all of those complications resolved and the patients recovered. There was only one recurrence, and that was seen in a patient with VHL, which is something that we very commonly seen. We know it's just a matter of time before another tumor shows up. And again, it's very important to follow up on our patients with VHL, just like we follow up on our patients without any syndromes or without any VHL disease. So these are really the three major series that have more than five patients. So we don't see this very frequently, but when we see it, we know that there is a way to deal with it and to attack the tumor and take care of the tumor in patients who have ablation and then have a recurrence. And again, we can either do a partial nephrectomy to save the kidney, or we can do a radical nephrectomy. The alternative would be to do a repeat ablation, but most patients, when the first ablation fails, don't want to have a second ablation, that the patient would say, well, I tried it once, it didn't work. Let's go ahead and do surgery this time. But of course, the option of repeat ablation is there, especially if the anatomy of the tumor and of the kidney favors that option to be done again. So moving from recurrence after ablation, I'm gonna talk about recurrence after partial nephrectomy. The incidence is about 5%, and the location could be in the kidney itself in the same area where the tumor was before, and that's probably because of residual disease at the time of surgery, and then that tumor grew back again. But because you're leaving the kidney there, you could have the possibility of having tumors in another location, that kidney, and that's not related to the first surgery. Or it could be around the kidney, or at lymph nodes, or in the adrenal gland. This is the Mayo Clinic series. These are our colleagues from Mayo Clinic, about nine years of data. These are patients who had partial nephrectomy the first time, and then they've reported on 48 patients that had a repeat surgery, or repeat procedure. In this series, initially the patient had a partial nephrectomy recurred, and then these patients were treated with ablation therapy. So these are patients who did not have a second operation but just had an ablation therapy to save the failure of the first procedure. The tumor size was small as it should be when we're treating with ablation. The complication rate was about five to six percent, and the follow up time in this series was 1.5 years. About 9% of the patients had another recurrence which shows that this therapy works, cryoblation after partial nephrectomy failure works, but we have to select the patient's well. The tumor has to be small, and it has to be in a good anatomical location to allow for successful ablation therapy. This is from our colleagues from the National Cancer Institute. This is a patient series that all of them had, or almost all of them had VHL, about 94% of the patients. 47 patients were included in the series, and here the difference between this series and the Mayo Clinic series that the patient had a partial nephrectomy the first time, they had a recurrence, and then the second time they had another partial nephrectomy. The surgery time again was quite long, 7.5 hours, and this is due to the difficulty from the scar tissue from the first surgery, but also because the patients usually have multiple tumors when they have VHL, so that takes longer time to remove from the kidney. Blood loss was almost two liters, and again, the average number of tumors removed was seven, just like the first NCI series that I showed you earlier. Average size again was about 3.5 centimeters. This is for the largest tumor in that kidney. Major complication rate was almost 20%. Three patients actually required radical nephrectomy and could not have partial nephrectomy either because of injury to the kidney during surgery or because the tumor burden was quite large and a partial nephrectomy was not possible. There was one patient who had a heart attack and died after surgery. Five-year follow-up and recurrences was about 20%, which again is not unusual in patients who have VHL. This is not something that we see in patients who have what we call sporadic tumors, basically one tumor. This is typical of our patients who have VHL disease. In this series, the only patient that passed away was the patient who had the heart attack. The other 46 patients were still alive after the second repeat partial nephrectomy, which again tells you it's just something that's doable. Currently, we're collecting our data and analyzing our series, and we don't have them at this point, but by next year's meeting, we should definitely have those available. So finally, I'll talk about recurrence after radical nephrectomy. This is the most rare type of local recurrence, and as I'll show you now, this actually has the most publications on it, and most publications have been in the single or two-digit number of patients, but we'll go over the details here in a second. The incidence is typically about two or 3%, so we can say safely it's less than 5%, and these are the series that have been published to date on treatment of local recurrence after radical nephrectomy. You could see here that most of the numbers go anywhere between 10 and 70. This is our series that one of our fellows, Arun Thomas just published just a couple of months ago, and I'll go over the details of that in a few minutes. This is the earliest published experience on treatment of local recurrence after radical nephrectomy. This is from our colleagues from California, from University of South California. They reported on 11 patients, 10 patients had no metastases at the time of the local recurrence, and most patients presented actually with symptoms, and that's why it's important when we talk to the patient to ask about symptoms, and for the patient to volunteer that information as well. It's not just looking at the CAT scan and just, okay, everything's fine, so we have to also listen and see what the patient has as far as complaints and issues. These presentations occurred at about two to three years after the initial surgery. The patients had surgery, but at that time, two out of the 11 patients who had surgery died after the operation, which tells you how serious these operations can be. Two patients died from the cancer at about one to two years after the operation, and three patients died of unrelated causes, causes not related to the cancer itself. However, at that time, four patients were still without disease at the last follow-up, which is a bit over 30%. This is one of our earliest series back from almost 20 years ago. We reported on 16 patients who had locally recurrent kidney cancer, and we found that you could still get cures in this patient population. Again, these were small numbers, and 15 patients out of 16 had a complete resection. Most patients had clear negative margins at the time, and at that time, 12 out of the 16 patients were still alive after the second operation. This is from our colleagues at the Mayo Clinic. This is about 15 years ago. Small series, again, showing that the best outcomes were in patients who had treatment that included surgery, and the worst outcomes were in patients who could not have surgery for a variety of reasons. This is the experience from our colleagues in London. Again, small series of 16 patients. Most patients were resected, and the median follow-up was short at about one year, but the relapse time, as you could see here, was about two months, so it was a short time to relapse. However, five out of the 16 patients were free of disease after follow-up, and this is after the second resection. This is our series that we just updated in 2015 and got published. This is over a 15-year, or 25-year period. This is the largest series that involved 102 patients who had surgery for local recurrence, and these are all patients who already had a radical nephrectomy and then had a local recurrence in the area of the operation. 84% of these patients had a radical nephrectomy at a different institution, and were then referred to our center for evaluation and treatment of the local recurrence. The time from the surgery to the local recurrence was about one year and a half, so this is when we see most of these local recurrences. They typically happen within the first two years, but they can happen any time. They can happen at four, five, 10, 20 years, and that's why it's important to keep following up the patients, but the majority of the recurrences happen in the first two years. Patients were typically young, age about 55. Most patients had an open surgery, and most patients at the time of the nephrectomy had aggressive disease, and about 20% had positive lymph nodes. 13% of the patients had positive margins. This is at the time of nephrectomy. This is before they came to us for the local recurrence surgery. Most of the recurrences, as you see here, were in the renal fossa, basically at the area where the kidney was, but 40% were in the lymph nodes, and 11% were at the adrenal gland. Again, all this is tumor at the area where the kidney was removed initially. At the time of the recurrence, 40% of the patients had symptoms, so again, it tells you that symptoms are very important to recognize and to report. The average size of the recurrence was about four and a half centimeters. Most of our patients had open surgery to treat the local recurrence, and about 14% of the patients had major complications, so that's why I think it's important for these surgeries to take place in a major referral center. Blood loss was less than a liter on average, and the average surgery time was about three and a half hours with a hospital stay of about one week. About 60% almost of the patients did have a local or had a relapse after the operation, but the average time to relapse was two years, so the patients were on average free of any cancer for at least two years after the surgery, and the survival after the second relapse was an average of about five to six years. So again, it tells you that surgery can help a lot of the patients with local recurrence, and what we found as predictors of a worse outcome was if the patient had positive lymph nodes at the time of the initial surgery or if the tumor recurrence was large, and that's why it's important to catch the recurrence when it's the smallest possible to treat it successfully if feasible. So last slide, I'm just gonna give you the take home messages. Local recurrences are rare, typically less than five to 10%, but they do occur, so we need to keep an eye to watch for them and to detect them as early as possible. That's why it's very important to follow up with the urologist that has been treating the patient in order to catch these recurrences and catch them early. It's best if these treatments are done in tertiary referral centers just because the complications of surgery can be significant, and because the surgeons in these centers typically have a larger experience with repeat surgery, with dealing with scar tissue, and again, having colleagues from other teams that could help with the surgeries if necessary. And surgery is doable in patients who have good performance status and who can tolerate surgery and who are willing to have surgery, and for recurrence after ablation or partial infractomy, the results are excellent with very high cure rates, and in patients who have recurrences after radical infractomy, the cure rate could easily be around 40%. Again, with the time to recurrence after the second time, could be an easy two years without any need for further treatment. So again, we do consider surgery for our patients with local recurrence with, in general, excellent outcomes. And these are our acknowledgments are my colleagues from Urology, Medical Oncology, Radiology, as well as Pathology and Radiology and Statistics who helped with all the information that I've presented here today. Thank you very much for your attention this morning. Does anyone have any questions for Dr. Brown? Yeah, I'll ask you in the mic if you don't mind. How fast does a recarment tumor grow in a year's time? It's very variable. So to give you a short answer, I don't know. Most of the times we don't watch those tumors, especially when the patients come to us, the tumor is already large. So the majority of the tumors that we find on a smaller size, typically we find those in our patients that we treated here because we keep a very close follow-up. In most of the tumors we don't watch, we just routinely go for surgery or treatment. So we only have a small number of tumors that we do watch initially. And it's very variable by the type of the tumor and by patients as well. So it's really hard to know exactly. I'm sorry, can you come? Do you sometimes do like DNA molecular changes? Yeah, so the question was, do we routinely do molecular analysis or DNA analysis on biopsies? So for local recurrences, we don't typically do that. A lot of times we don't even do a biopsy. If the recurrence is large and it is very suspicious for kidney cancer and it's not supposed to be there, typically we just go ahead and do surgery. Sometimes we do a biopsy to be sure, especially if the tumor is on the smaller side. But in general, the DNA analysis is not done routinely. We typically do those analyses if we have exhausted a lot of the treatment options, the drugs, and now we're looking for a different drug to use and we're trying to use the DNA analysis for to guide us in what way to go. So this is typically done in a later stage of the treatment. Thank you.