 All right. Good morning. I'd like to thank the Kidney Cancer Association for inviting me to talk. We're going to switch gears completely. Brian was talking about small local eyes, and we're going to talk about the patients that have locally advanced renal cell cancer. I'd also like to take a moment to sincerely thank our patients. You provide us so much inspiration and show us how to improve, and I just wanted to take a moment to thank you for that. So we'll talk today about patients with tumor thrombus, patients with lymph node involvement of their kidney cancer, and then invasion of adjacent organs. When we talk about venous invasion or tumor thrombus, it occurs in about 10% of patients with kidney cancer. It makes surgery more complex, and the thrombus may be confined to just the renal vein, or it can actually travel all the way up and be into the right heart, which obviously increases the complexity of surgery. And you can see that the thrombi can be either free-floating, so something you can pull right out, or they can actually be attached to the entire large vein going back to the heart. Patients present with different symptoms, swelling in their legs, blood clots in their lungs, sometimes just protein in their urine. Sometimes patients are completely asymptomatic. This is a patient who has a thrombus. You can see that extends up actually into the heart, and the only symptom he had was some dilated veins on his scrotum. So when we look at surgery for patients that had venous thrombus, some of these were done in the early 20th century. It's really impressive to think that anesthesia was really at its infancy at that time, and they were doing these surgeries in some cases successfully. The rationale at that time was that in non-metastatic patients, if you could remove all of the tumor, about half of those patients would be cured with surgery alone. And then surgery also provided a palliative benefit and local control to prevent the thrombus from extending up higher. These are still true today. So it's really important when we evaluate patients before surgery that we have a multidisciplinary approach. We invite the anesthesia team, medical oncologists, sometimes vascular surgery, cardiothoracic surgery, liver surgeons, or transplant surgeons, and that we get a really comprehensive workup before we do these surgeries. High quality imaging is critical for planning surgery depending where you're at. This might be an MRI or a CT scan, and then we also intraoperatively will use a transesophageal echocardiogram to monitor during surgery. This is a case, and I've changed the names, but these are all real cases. Mark is a 54-year-old gentleman who presented with lower extremity swelling. He has a tumor in his left kidney, you can see, and then he has thrombus throughout his inferior vena cava and actually extending into both of his legs. This is an MRI image that also shows that his left renal vein with the thrombus went behind the aorta, which increases the complexity even further. This is a 4D MRI, and I'll have to to acknowledge and thank our medical physics department and our radiologists for developing all of these techniques, but it can show the blood flow around these thrombi and into the arterial portions as well. You can see here this is actually tracking the individual particles through the vessels. You can see the absence of blood flow. Let's see. Can you play that one more time? There's always a problem when you try to put a video into a talk. What we're showing, and you can just leave it on this, you can show the arterial blood flow and this guy actually did have a duplicated renal artery. The area that's highlighted in green was the inferior vena cava that we actually completely removed and then put a graft of a bovine pericardial graft that's going back up to his inferior vena cava connecting it to the rest of his circulation and we removed out all that area of his tumor. He's doing well about six months after surgery, but it really highlights the advantages of having these techniques preoperatively. It's also really important to look during surgery to monitor these patients closely, to look for an increase in the thrombus height, to evaluate the fluid management, and to look for tumor embolization when you have blood pressure shifts. This is a patient we operated on last week. She had a level two IVC thrombus. You can see that she's developed extensive collateral circulation. The blood is shunted to other areas because it's no longer able to get back to the heart through the inferior vena cava. This is her intraoperative monitoring. You can see that little area within the IVC around those red dots there is the thrombus and then this is after we compressed and put clamps across that to remove it. This is something that's invaluable to us when we can look at the patient's blood pressure and correlate it with the findings on the TE. There's a lot of different classification systems for how high the tumor thrombus goes. Most commonly we use the nevus system. For patients with level one or level two thrombus, we basically place clamps on all the inflows and all the outflows and make an incision in inferior vena cava and pull it out. Sometimes we have to resect an area. Sometimes we have to graft an area if we've removed too much of the IVC. As the thrombus heights get higher, if the tumor goes above the hepatic blood supply, at this point sometimes you really need a multidisciplinary approach to include the hepatic blood supply for a few minutes. And as the tumors get higher and even approach into the right heart, this is really a time sometimes you have to have the cardiothoracic surgeon come in. You can either do a sternotomy or you can come from below and pull this out of the heart. But this definitely increases the risk of bleeding, stroke, and cardiac dysfunction afterwards. So we'll just kind of review some of the more contemporary data for renal cell cancer with thrombus. What's the best strategy to look at vein margins? We all know we want to remove the entire, you know, the entire area of cancer. And if there's any margins in the vein walls, how much of a problem is that? As surgeons we macroscopically always remove that, but how important are the microscopic vein margins? So this is a project I did when I was a fellow with Dr. Wood, but looking at the microscopic invasions of margins that where we were resected. And what we found was that in general margins we always try to avoid them, but margins are less a marker of where the tumor is going to recur in an isolated fashion and more a marker of aggressive disease. So what's the best strategy? We should remove all macroscopic tumor, and it's definitely prognostic for aggressive tumors. Occasionally we will do frozen sections of the walls, so we'll look pathologically interoperatively, but more often we'll do a wide excision with a reconstruction replacement as necessary. This is a study out of the Mayo Clinic, again looking at some radiographic factors, looking at right-sided tumors, the diameter of the area where the renal vein enters, the inferior vena cava, and then complete occlusion. And they found that if you had two or more of these predictors, or sorry, all three of these predictors, then your risk of needing reconstruction was much higher, so this helps us plan for surgery. So what about patients that present with pulmonary emboli? We think this is about 5% of all patients, and traditionally these patients are thought to have worse outcomes, or anesthesiologists will tell us that these patients have a very high surgical risk, and they quote that from non-renal cell cancer patients. But are these patients really at a higher risk? And so we looked into this, and this is a collaborative effort between the University of Wisconsin, UT Southwestern and Indiana Anderson, and we looked at 782 patients, and about 4% of those patients had a PE prior to their diagnosis and prior to surgery. So we found no difference in their 90-day mortality in the patients who presented with a PE, and no difference in the cancer-specific outcomes or the recurrence rates. So this is important because these patients should be offered surgery if it can benefit them. And again, this is showing over time about 63% of these patients who did not have metastatic disease, did not have recurrence after surgery. So what about using pre-surgical targeted therapy? This had been a thing that was very talked about, and there were a lot of different case reports, many publications talking about shrinking the tumor using targeted agents. But we really need to consider how often does it respond? Does it shrink enough to change the surgical approach? Are patients able to tolerate the adverse effects of systemic therapy? And is the risk of deferring surgery outweighed by the risk of the thrombus extension causing hepatic or cardiac dysfunction? So several studies have looked at this. They're not large studies, but kind of multi-institutional studies, and showed that few of the thrombi actually decreased enough to change the surgical approach. And so the majority of patients should not get neoadjuvant chemotherapy to shrink the thrombus specifically. There are certainly some patients that benefit from neoadjuvant therapy, and the theoretical benefits are greatest in the patients with highest level thrombus because potentially these patients could avoid cardiac bypass. So what about patients with the highest level IVC thrombus? This is less than 1% of all patients with renal cell cancer. It's really the thrombus that extends above the hepatic circulation and sometimes into the heart. What are the risks? There's really a lack of high quality data. This is a chart that just kind of shows the studies that had looked at this prior to 2012. And if you look, these are all large time periods, meaning that patients that got operated on in 1970s were very different than the patients that got operated on in the 2000s. They're all small studies, and they have very different definitions of how mortality is defined. And these are data. These are things that people want to discuss prior to surgery. So again, we collaborated with four institutions, the Mayo Clinic, MD Anderson, Southwestern, and University of Wisconsin. We looked at 162 patients and their outcomes from 2000 to 2012. And then we classified the complications and the mortality within 90 days. So we found about a third of these patients had major complications within 90 days. Independent preoperative predictors of that were the highest level thrombus as well as systemic symptoms. There was no difference in the complication rates or perioperative mortality for patients who had cardiopulmonary bypass. It looks like that was not as much an important factor as the patients themselves. And so we found about a 10% mortality in about 90 days, which is something that I think people want to discuss prior to surgery. This is potentially a life-saving surgery, but it's also a very, you know, somewhat risky surgery in hospitals in the modern era. This is our proposed management. It hasn't changed very much. If you have metastatic disease, we recommend a multidisciplinary consultation. And really surgery at an experienced center is key for this type of surgery. So just for a couple of minutes, I wanted to talk about sederidectomy nephrectomy for patients who have a tumor thrombus. This is again a multidisciplinary, I'm sorry, multi-institutional series of 427 patients treated at several different centers. We looked at the thrombus level as well as risk models that were calculated preoperatively and looked at overall survival in these patients. So only for the patients who had IVC thrombus above the diaphragm was the survival statistically worse. So patients with IVC thrombus below the diaphragm or patients with renal vein-only thrombus did better than the patients with thrombus above the diaphragm. We looked at the MOTSER criteria, the MSKCC criteria, which were prognostic as were the IMDC criteria, as were the criteria developed at MD Anderson by Steve Kulp in the cancer paper in 2010. So these were all predictive of whether or not patients did well after surgery. What we found, the one striking thing is patients most likely to have an early mortality, meaning less than nine months following sederidectomy nephrectomy, were patients with sarcomatoid features or patients with the highest level IVC thrombus. It's also important to note, this is the series of patients where it says current series, that these patients had as good survival or better than some of the population-based series of sederidectomy nephrectomy. So just because you have a tumor thrombus does not mean that your survival is going to be any less than someone else with sederidectomy nephrectomy. In fact, it looks like it's slightly better in some of these risk categories. So the conclusions about IVC thrombus patients definitely increases the complexity of surgery and the risk that there's going to be complications afterwards. It may provide a durable cure. So there's definitely a rationale to do the surgery in patients, especially non-menostatic patients. Upfront surgery is really the standard of care with patients who have venous thrombus. Many patients who present with a PE do just as well as the patients that do not present with a PE. And we really have to consider individual patient and tumor characteristics for sederidectomy nephrectomy. So what about renal cell cancer involving the lymph nodes? So this is data from Dr. Blute in 2004 showing that patients who had lymph node involvement do a lot worse than patients who don't. This is a patient of mine who's 25. He had a renal mass and he's isolated in large lymph nodes. You can kind of see right along the aorta there. And he had had the patient weighed, I think, 510 pounds. He's had multiple abdominal surgeries for congenital abnormalities as a child. This is his pathology after surgery. We did a full lymph node dissection, grade three renal cell cancer, metastatic cancer involving one lymph node. This is him three years later with no evidence of disease. Excuse me. And again, this is somebody, anyone that operates on patients with kidney cancer has patients like this. So the argument's for performing a lymph node dissection in high-risk non-metastatic patients. Potential improvement in survival, but there's also some non-metastatic patients that are cured with surgery. You'll see that it's a low rate, but it is some. So we really have to acknowledge that most of these studies are retrospective small numbers of patients. There's definitely selection bias in patients undergoing lymph node dissection. And there's really a lack of a standardized surgery used by different surgeons. So this kind of skips to the chase. Do patients benefit from lymph node dissection? We know that most patients with small organ confined tumors, there is randomized data for this, probably don't benefit because they rarely have lymph node metastasis. Maybe some patients with metastatic tumors benefit, but there's less data for that. There's definitely some data showing that patients without metastatic disease who have isolated lymph node metastasis would benefit. We know that locally advanced patients have the highest risk of recurrence, and this may be the best chance to surgically interrupt an advanced disease processed. We also know that metastatic spread throughout lymph nodes is not something that we can predict easily. About half of patients with metastatic cancer never have lymph node metastasis. So this is the only randomized trial. Again, at 772 patients, about 70% of these patients had T1 or T2 tumors, so these are not high risk patients to begin with, and only about 3% of these patients had metastatic disease. So it's hard to really conclude anything from this study, other than that there was no difference in rate of complications between groups and lower risk tumors probably don't benefit from node dissection. So can we identify patients before surgery who might have lymph node metastasis? This is a study by Dr. Blute. He looked at these five high risk characteristics and found that they are predictive. This is a study following up on that. In patients who had two of those five high risk characteristics, about 40% of those patients had pathologic lymph node metastasis, and only about a third of those were seen on preoperative imaging. This is another study, which again confirms those five criteria. So which lymph nodes need to be removed for kidney cancer? It's difficult because most lymphatics flow with the arteries, but it's very variable. Also there's a lot of neovascularity, a lot of new blood vessels that are built around these tumors that can alter the drainage patterns, and the lymphatic drainage of the perinephric fat is not the exact same as the kidney. There's also some direct connections to the chest. So really there's no consensus on the extent, there's no standard dissection. We know that just removing the lymph nodes around the kidney is not adequate. About 45% of patients with lymph node metastasis did not have metastasis just in that, in the hyalur region right around the kidney. So this is a map of some lymphatic metastasis in the study. Again you can see it's pretty variable for left and for right-sided tumors. This is a proposed extended lymph node dissection that I think many of us still use for the right-sided tumor as well as for a left-sided tumor. So moving on to some of the contemporary data for lymph node dissection. Dr. Gershman is at Rhode Island, but when he was a fellow at the Mayo Clinic, he used some very fancy analysis to look at some of the more retrospective data. And using propensity score matching, didn't find a difference in outcomes for patients who got a lymph node dissection versus patients who just got a radical nephrectomy for renal cell cancer. This is another study from the same group, but again looking at patients who had 138 patients with just lymph node metastasis. So patients with no other cancer in their body. And of those patients, 16% had no cancer in their body at five years. This is very similar to other reports. Scott Delacroix in general urology 2011. And even more important, 15% of those patients at 10 years had no other cancer in their body. So about one, you have to do about six or seven lymph node dissections to get one patient like this that's free of cancer at 10 years, but it definitely does seem to make a difference. So this is a systematic review and a meta-analysis kind of trying to compile all the data. Again, lymph node involvement is associated with the worst prognosis. There's minimal data to support a therapeutic benefit in patients who have any type of renal cell cancer, but this high-risk group of patients may warrant further study because a subset of these patients do have long-term survival after only surgical resection, which I think is important. So the take-home points, again, poor prognosis for lymph node metastasis, but this small proportion of patients have a durable disease-free survival. And we can't really predict who that is prior to surgery. So the last few minutes I'll talk about direct-invasion renal cell cancer into surrounding organs. So these are both patients I saw in the last month that this patient in their left kidney has direct-invasion into their pancreas and into the splenic hyalum. This is something that surgically is a feasible resection as far as we could remove this, remove part of the pancreas and the spleen and get negative margins. This patient has no other cancer in their body, and so did well on his recovering after surgery. This is kind of the opposite end of the spectrum. This is a lady who had a tumor in her right kidney, and you can see it involves a significant proportion of the liver. When we mapped out the amount of liver that would have to be resected, it was really not feasible from our liver surgeon's standpoint to remove that much of the liver at the same time. So this lady has been referred to our medical oncologist and is undergoing pre-surgical targeted therapy. We know that this is probably the most rare of the things we're talking about today. Only 5% of patients. Metastatic disease is very common in these patients, and these patients rarely do well if they have adjacent organ involvement and metastatic disease. We know that in general renal cell cancer is more likely to compress other structures rather than invade them, so this is something that's rare. It's associated with a poor prognosis, a five-year survival of somewhere between 5% and 18%, but complete surgical excision is really the only chance for cure in these patients. We know that getting negative margins in these patients is very important. So the most common organs at risk are the adrenal gland, the posterior abdominal wall, the muscles, including the diaphragm that's around the kidney, the liver, the spleen, the duodenum, the pancreas, and sometimes the colon. This is a study in 2009, and really there's not a lot more recent data, but showing that the liver was the most common organ in the series affected. About 37% of the patients had positive surgical margins, so it's very difficult to, and you know, the surgeons are trying to spare the other structures in there, but if you can't spare the other structures, this is really where I think neoadjuvant therapy has a role. Surgical margin status was the only significant factor for recurrence in death, and patients who had metastatic disease did very poorly with an immediate survival of only around six months. So can we predict invasion pre-operatively? Vitaly Margulis looked at patients who had clinical invasion of other structures, and of those 30 patients, 60% of them did not have pathologic involvement. So it was difficult to predict prior to surgery whether or not the adjacent structures were invaded. Now on the two patients we showed, the one with the liver is kind of not in doubt, but the patient with the pancreas involvement, even if they did have more significant involvement, we could have removed a significantly larger portion of the pancreas. So kind of to summarize, kidney cancer compresses more often than it invades. There's a poor prognosis with invasion of adjacent organs. Majority of patients with T4 disease also have metastatic disease. Surgical resection really offers the only chance for cure. There's really studies lacking for patients with this type of tumor. Neoadjuvant therapy may decrease the complexity of surgery in some patients. Okay, so this is my final slide. This is some new data from the Fox Chase Group, and they looked at the National Cancer Database patients with metastatic kidney cancer and looked at several different cohorts. And you can see on the x-axis down there, that's the volume, that's the number of kidney cancer patients you saw per year. And then the one year survival is on the y-axis. And you can see as you go to a more experienced center, your chance of having a survival more than one year is almost doubled in some respects. So this really points to the fact that going to an experienced center is really key, having a multidisciplinary interaction and discussion of your disease. Sometimes surgery is the right choice, sometimes it's not. But you really have to have the experience to know when it is and when it isn't. Oh, actually this is my last slide. So this is a patient I had who we removed his kidney and I love this tattoo. It says, gone but not forgotten. You can see that. Thank you.