 I would like to thank Chris and the Kidney Cancer Association for the opportunity to be here today and to present this topic on the management of locally advanced kidney cancer. So this is in a way the other spectrum that Dr. Metin just presented. The first talk was in small masses. This one will be on larger tumors and more advanced disease. So just to define advanced kidney cancer, one way to define it is if you have a direct invasion of the cancer into the inferior vena cava. That's the big vein that drains blood and goes back into the heart. And kidney cancer in about 10% of the patients likes to go there. The other disease entity is invasion from the kidney itself into nearby organs such as the adrenal gland, the colon, the pancreas, or others. And this is considered to be stage four disease. Another entity is a spread of the kidney cancer to lymph nodes around the actual kidney. And this is still considered stage three. And finally, local recurrence, which means the kidney has been removed either partially or completely and then disease recurred in that same geographical area. So I'm going to start first by talking about invasion into the vein, either the vein of the kidney called the renal vein or the big vein called the inferior vena cava. And this is one way to classify it, and this is described by the Mayo Clinic. As you could see here, level one is gone from the kidney into the renal vein and barely into the vena cava. Level two has gone into the vena cava but still below the liver. Level three is above the veins of the liver but still not in the heart. And level four is gone already into the heart. And this is by direct extension, as you could see here. And as I just mentioned, this entity of a tumor thrombus, which is a tumor inside the vein, occurs in up to 10% of patients with kidney cancer. And aggressive and complete resection are very important and can provide cure in up to 70% of patients, especially if there is no signs of spread or metastasis outside of the abdominal area. This is our experience here over a period of about 16 years, about 600 patients with invasions into the vein. The median age or the average age of about 60 years with a follow-up of about two years. Tumors tend to be large, about 10 centimeters on average, and most of them are clear cell tumors, which is the most common type of kidney cancer. As you could see here, most of the tumor into the vein is limited to the renal vein. The next would be going into the vena cava but still below the heart. And the minority, thankfully, is gone into the heart. These surgeries are big surgeries. The average blood loss is almost a liter. The surgical time on average is about three hours. Hospital stay is about a week. So this is not a simple operation and definitely not a simple recovery for our patients. Complications in the first 30 days could be as high as 25%, and I'll go more into the details of complications later. And as far as survival, if there is no spread of cancer elsewhere, the average survival is about five years. And again, these are all averages, all the numbers I'm giving. And if there is spread into lymph nodes or elsewhere into distant areas, such as lung or bone or liver, the average survival is about 15 months. And these are what we call predictors of survival. So this helps us try to identify what patients might benefit from surgery or might live longer depends on some factors, such as if you have the clear cell type, there is a higher chance of surviving after surgery. If you have a high grade, which is a grade four or sarcomatoid or invasion into the fat of the kidney or spread into the lymph nodes, the chance of survival becomes less compared to if you don't have any of these. Typically, this is a big operation. We do them through large incisions, either sideway incision or up and down incision. And it doesn't really make much difference. It depends on the surgeon preference at that point. This is our experience with more advanced tumor thrombus. This has gone into the vena cava or the heart. Again, the average age, as you could see here, about 60 years. Hospitals stay about a week, and the average follow-up is about two years. And you could see there's a large number of complications that could happen after these surgeries. About half of them are considered to be minor complications. The other half are considered to be major complications. The complications that occur in the first month after surgery are mostly related to lung function. For example, if the patient's not breathing deep enough, they could have a telexacis or what is considered to be compression of the lungs. The lungs aren't opening enough to supply good oxygen or pneumonias or problems with the kidney function or problems with intestines such as inability to go to the bathroom. And these are things that keep the patients longer in the hospital. These are complications that happen after 30 days. So typically, at this point, the patients are at home. Most of these complications are minor, but there are some major complications as well. So the most common one is chronic kidney disease, which makes sense because the patient now has one kidney. So that is one of the side effects of these kinds of surgeries. Again, the predictors of complications are mostly age is the more significant one. So the older the patient, the higher the chance of a complication happening after surgery. And in some patients, there is also a risk of dying after surgery. It's a small percentage, but it's something that we discussed with the patients before undergoing such a procedure because it's very important for the patient and the family to understand that there is some risk involved with these kinds of surgeries when the invasion is quite deep into the big vein and going into the heart as well. This is the second topic as far as the advanced disease. So the first one was tumor going into the vein. This one is tumor going into adjacent organs. This is a CAT scan that you see here of the tumor in the upper portion of the right kidney, and it has invaded directly into the liver. This is not a spread through the blood into the liver. This is a direct extension of the liver. And this is the patient that had this operation, and this is done in conjunction with one of our colleagues from the liver surgery team, and here we removed the kidney with this part of the liver as well to make sure we got all the tumor out. This is considered T4. T stands for tumor. T4 means invasion into adjacent organs. This is a curve called Kaplan-Meier curve, and one of my colleagues, Dr. Chapin, will describe this in a bit of detail later today. On the y-axis, you have survival. On the x-axis here, you have just time. The lower the curve, which is T4, the higher the chance of not surviving this disease. So here you see T1A. These are the tumors that Dr. Matine just described. These are the small localized tumors. The T4 is this curve here, which is the bottom curve. This is our experience here over a period of 16 years with 30 patients that we thought had invasion into other organs. This is why we're using the word clinical. So we looked at the CAT scans. It seemed that there was invasion into other organs. We took all these patients to surgery, and thankfully, only 40% of these patients had true invasion to other organs. So in other words, 60% of the patients did not have such invasion. So these are patients who are considered to be over stage. So again, we thought they were T4 or invading other organs. We took them to surgery, and we found that 60% of them did not. The most commonly invaded structures, as I wrote here, are colon, pancreas, and diaphragm. But there could be invasion into other organs, such as small intestine or major vessels as well. And as you could see here, the recurrence of the disease is higher if you have true invasion into other organs. The average is about two months of the cancer coming back if there is true invasion versus about one year or more if there is no true invasion into other organs. Again, this is another curve that I just showed. And again, saying the same thing that survival is lower if you have true invasion. And the risk of recurrence of the tumor is higher if you have true invasion into adjacent organs. And we found here that other factors that affect survival in this patient group are invasion into lymph nodes. So typically, if the tumor has gone to the lymph node, the survival is lower. Again, these are the summaries from this study is that 60% of the patients initially thought to have invasion into other organs were found not to have such invasion when actually they were taken to surgery. And we could not really predict who these patients are. So we basically have to take these patients to surgery in order to find this information. But if you think about it the other way, if we don't take these patients to surgery, we are letting down possibly 60% of the patients that we're not operating on. Because really, they didn't have any invasion. And here, just to show you that the recurrence rates are higher if you have true invasion. And still, a significant proportion of patients did benefit from such aggressive surgical resection. Now moving on to the third topic of locally advanced disease, this is the spread into lymph nodes. This is a large tumor here you could see on the CT scan of invading the right kidney. Again, this is the same tumor with a lot of lymph nodes being involved. And this patient had surgery with complete removal of the tumor and complete removal of all the lymph nodes. There was, as you could see in this picture, the liver, which is here, is very close to the kidney. And it might look like it's invading, but there was no invasion at all into other organs, just the lymph nodes. However, the presence of spread into lymph nodes is a serious condition. It does decrease the survival of our patients. And this is the average five-year survival, can be anywhere from 0% up to 20% in this patient population who has invasion of the lymph nodes. And this is our experience with removal of kidney tumors, such as the one I just showed, who have only invasion of lymph nodes, but no spread anywhere else. So we looked at our database of patients. We have about 2,500 patients who had no metastatic disease. This is where the M0 stands for. M is for metastasis. And we found that 2.7% of the patients had positive lymph nodes, which is spread to the lymph nodes, without evidence of spread anywhere else in their body. The average age is, again, the same as I showed earlier, about 58. The tumors are large, about 11 centimeters. Most of the patients have good performance status, meaning that they don't feel anything for the most part. But we have here about 2 thirds of the patients have some sort of a local symptom, maybe a little bit of pain, or maybe some blood in the urine. And here you could see that when we take these patients to surgery, the results after surgery, the survival is about 37% at five years, which is a good number, considering that these patients had aggressive spread of the tumor to the lymph nodes. And the recurrences that happen after surgery, you see about 50% of them happening early on, but about one third happen after one year. So in that one year period, these 33% of the patients had no disease. And the locations of the recurrence, if the recurrence is meant to happen, about 40% happens in one location, and the rest occur in more than one location. And this is what we found as far as the factors that can predict were how do we know if a patient is going to do well or not. If they have the papillary histology, as I mentioned earlier, I mentioned the clear cell type, which is the most common type. The papillary histology is the second most common type. So we found that if you have the papillary type of tumor, if you have only one lymph node involved and not more, this actually is a good thing that you might have longer survival. However, if you have the sarcomatoid type, this is a very aggressive tumor, and that could decrease survival. And the better the patient feels, the better the patient will do after the surgery. So the patients who feel bad before going to surgery sometimes don't do very well after the operation. And again, this is the result in patients who had an operation. About 45% of the patients had no disease at 12 months, on average, and about 22% were disease-free on long term at a median or an average follow-up of about three and a half years. So again, a group of this patient population benefits from aggressive surgical resection, and we have some ways, albeit a bit crude ways, to try to predict which patients might benefit from such an aggressive operation. So again, surgery does help a group of patients with no positive disease, especially if there is no spread elsewhere. And these are the predictors of who might benefit from such an aggressive resection. Again, it's patients who have a papillary type, patients who all the disease have been removed surgically with negative margins, if they have a low number of lymph nodes, if there is no sarcomatoid disease, and if the patient has a good performance status, which means the patient is doing well in functioning normally. And the last and the fourth topic is the topic of local recurrences. Again, this is for patients who had surgery already, and then during follow-up were discovered to have a recurrence in the area of the operation. So if they had a right kidney removal, or as in this picture here, a left kidney removal, you could see here there is a recurrence of the tumor where the left kidney was. Again, we looked at our database, and this is our own experience here of almost 3,000 patients who had complete nephrectomy with the intent of cure. And we found that actually a very small percentage had local recurrence. 1.8% of this large number of patients had a recurrence at the area of the operation. About 60% of the patients had symptoms. These symptoms could be either local, such as pain, or blood in the urine, or whatnot. But some patients have systemic symptoms, meaning fever, or weight loss, or just not feeling good. And from our study of 54 patients, we found five risk factors that tell us that the patient might not do very well after surgery. And these are a large tumor, a large size of a recurrence. If the margins were positive, which means if the tumor was not completely resected, again, you see here the theme of the sarcomatoid element. If you have a sarcomatoid tumor, typically the recurrence rates are higher. And if you have these two blood tests, the LDH and the alkaline phosphatase being abnormal. So if you have none of these five risk factors, the average survival is very good. It's 111 months. If you have one of these risk factors, it's about three and a half years. And the average survival, if you have more than one risk factor, is typically less than a year. And this is from the study that we found that disease recurred in about 2 thirds of the patients after aggressive resection. And the isolated relapse or recurrence in that same location is about 15%. The survival without a recurrence was about a year on average. And the survival from a cancer standpoint was about five years in this patient's subpopulation. Again, this is a very rare entity, as I mentioned, about 1.8% of their patients. Just as a final summary of all these four topics, aggressive and complete surgical resection when feasible should be done or should be considered in patients who have a good performance status. Again, patients who are feeling well and functioning normally, and especially if they have limited spread elsewhere, limited metastatic disease. So if the disease is in the area of the kidney and the abdomen, we should definitely consider aggressive and complete removal. As I showed from one of our studies, unresectable kidney tumors are extremely rare. In other cancers, this is a more common problem, but a tumor of the kidney that is not removable by surgical technique is extremely rare. So typically, if somebody tells a patient, your tumor cannot be removed because it's unresectable, that patient should at least seek a second opinion just to make sure that this is the right thing. And as I showed you, we are fooled by the CT scan 60% of the times that we think the tumor is invading other organs, but it's really not. And the only way to know is to do the operation. And for the surgeons, it's very important to be familiar with distorted anatomy, with these large tumors, and with these large lymph nodes, and with advanced surgical techniques to try to get the best outcomes for our patients. And this is truly a multidisciplinary teamwork. This is not the work of only the urologist. This is the work of the radiologist who's helping us identify things before surgery. Our colleagues from medical oncology to see if the patients need treatment before or after surgery, and also our colleagues from other surgical departments, such as the intestinal surgery, the liver surgery, the vascular surgeons who help us with these types of big operations. And again, I think it's very important to avoid surgical nihilism in patients with locally advanced kidney cancer. So just because you have a very big tumor doesn't mean that there is not a potential for cure. And that's why if a patient is told you can't have surgery or you shouldn't have surgery or we can't remove the tumor, the safest thing is to just talk to another doctor and then get their opinion just to be sure that this is truly the right thing to do or not. Thank you very much for your attention.