 So, so let's move on and we'll have more time for discussion So we're going to turn our attention to surgery and radiation therapy surgery first Hyun Kim who's the surgical director of uro oncology and trained at UCLA among other places and then went to Roswell Park and arrived Back at Cedar Sinai. How long ago, Hyun? Six years ago. Six years ago is just an outstanding surgical oncologist One of the few urologic oncologists in the country that has both a laboratory-based program as well as Spending time in the operating suite. He's going to talk to us about the surgical approaches. Thanks, Hyun Thank you, Bob. I want to also thank Bob and Nancy for the invitation. It's always a pleasure to give this talk to patients because, you know, it means something different to patients than to other doctors. It's less theoretical. It's more real It's more practical and And you know, whatever we discuss today patients remember not like doctors So with that I Let me talk to you about something that's near and dear to my heart surgical approaches. So Bob talked about curing kidney cancer When the cancer is localized to the kidney, we can cure it. It does involve surgery when it's metastatic Surgery as Dr. Hoffman mentioned has a role, but its role is different. The goals are different. So I've outlined for you briefly The topics that I'm going to discuss One is a surgical management of the low-risk localized cancer where we can clearly cure the disease I'm going to talk very briefly about adjuvant therapy. You're going to get a whole talk on this I'm only going to show you three slides mainly to transition into the last topic, which is The current status and research going on in biomarkers and this is something that my laboratory works on and Something that I have a passion for So when we talk about localized cancer, we're talking about something like this so this is a CAT scan and many of you have had CAT scans and This is a cross-section of the abdomen and the kidneys are here Two kidneys and this is what a normal kidney looks like it's borders are smooth There's some fat in the middle the blood vessels are here if you look at the Kidney on the right as you come around the border you see this round tumor and that's the kidney tumor that is Enhancing indicating that it has a blood supply. It's solid and so it's very worrisome at least on imaging from malignancy So this is a tumor. We would treat surgically. I Want to make a brief case for doing a partial nephrectomy for that patient as opposed to a radical nephrectomy Which would involve removing the entire kidney So when we Do these operations in some cases we make a large incision. This is what we call an open approach and in order to get exposure sometimes we have to remove a rib sometimes we We can leave the ribs in place But in all cases we have to cut through a lot of muscle we put retractors in In order to have space to operate and if you're pulling and Stretching the ribs and muscles for four hours. Sometimes it's not surprising that you wake up from surgery with a lot of pain There's no such thing as painless surgery, but if you do laparoscopic surgery the tissue Undergoes a lot less trauma So we put a couple of these troll cars in and you literally make keyhole size openings There's less stretching of muscle less less cutting of muscle these troll cars actually go in and Rather than cut muscle They simply split the muscle and then they go right between the muscle fibers And so there's a lot less pain postoperatively and As you can see here, you don't You're you don't end up with the shark bite This patient actually has a hernia over his incision and so there's a little deformity And that's something that may require additional surgery to repair This patient had laparoscopic surgery and six months out the incisions are barely perceptible And so for younger patients that were curing were cosmetic Outcomes are much more important Laparoscopic surgery clearly has that as an advantage as well And There is something called robotic surgery There's a machine that's currently widely in use It's called the Da Vinci surgical system made by intuitive surgical now. This has a lot of commercial appeal sex appeal if you might if you could if you want to say because You know who wouldn't want that their operation for done with the robot So this is a system that was actually designed for military use initially So the thinking was you know the frontline. It's dangerous. We don't want the doctor getting shot and killed a military unit may May not have very many doctors as part of their group So it's key to keep the doctors safe you keep them behind the front line But you could send the robot into the front line and the robot could be hooked up to the patient The doctor is way back, you know Where he can't get hit and they would do the operation. Well as it turns out these Robots are extremely delicate and sensitive and so Sending it out and they cost a couple million dollars and it was questionable whether the doctor was cheaper The robot was cheaper to send to the frontline. So in any case the military use is gone it's now used in the civilian setting and It allows doctors to do the operation with Greater accuracy and better visualization now having said that in my practice, I don't use the robot very much because We do laparoscopic surgery and this is really another way to do laparoscopic surgery and And it's an expensive piece of hardware. We have it. We use it sometimes But in many cases we can accomplish the same thing with pure laparoscopy with a lot less Cost and and with the much simplified surgical process All right, so if you do a partial kidney removal this cartoon kind of shows you what happens. So you're Your kidney is here and the tumor is here and you're using Laparoscopic instruments. They're kind of like chopsticks and with little Working working Instruments at the end and here you're sucking the blood you're cutting the Tumor out and then after the tumor is gone you have to sew the kidney and you're suturing and tying and This allows you to preserve the kidney and take only the tumor out If you look at practice patterns at Not just any hospital, but mainly at centers of excellence teaching hospitals and big universities you see that over time the Number of partial nephrectomies has increased. So if you look from 2005 and 2009 You can see that the percent of kidney Surgeries nephrectomies that are partial as opposed to radicals has been increasing and Since 2009 most renal surgeries for local tumors has been a partial nephrectomy and not a radical nephrectomy Now this will never get to a hundred percent because there are clearly tumors that are so big that there's not enough kidney to preserve There are tumors that are so big that the entire kidney has to come out This is a busy slide, but I've circled the numbers. I want to draw your attention to so if you take patients who have Normal kidney function before their operation and then you look to see how many of these patients have abnormal renal function post-operatively The numbers are shown here. So after a radical nephrectomy 58% of patients who started with normal kidney function are now Classified as having renal disease because of poor renal function If you do a partial nephrectomy that number is much lower at 15% This is really the main reason we try to preserve as much of the kidney as possible during the operation Here's an interesting study that came out in 2004 and made us and further Provided a push to do partials. So on on this side is the kidney function So kidney function is measured as GFR and you can see that kidney function is decreasing as you go along the x-axis Y-axis is the rate of cardiovascular events mainly heart attacks And what you see here is that as your kidney function decreases your risk of heart attacks increases so The question was is this a correlation or a cause and effect Relationship so in other words, do people who have renal disease also have heart disease or Does renal disease somehow cause you to have heart disease, right? So that was an unanswered question and it was really because we didn't have the answer we Our initial response is to do more partial nephrectomies and I think that was the right thing to do and But the but the answer to this question is there a cause-and-effect relationship is Probably maybe not and I would give you the One piece of data that we have that suggests that it's more a correlation and not a cause-and-effect relationship So this is a larger study that has ever been done comparing radical and partial nephrectomies And it was done in Europe. It was a study that involved multiple centers and it was Closed in 2003 after 541 patients had been enrolled although the US participated We just we weren't very good at enrolling patients onto these trials And we can talk about that another time, but this is largely a European study Hmm and in the study if you compare the radicals and partials there was really no difference in the number of heart attacks so if you Believe that Decreasing kidney function because of a radical nephrectomy causes heart disease you would have expected that with long-term follow-up This group would have had more heart attacks, but that wasn't the case and so You know at this point the best evidence is that a slightly decreased renal function doesn't put you at a higher risk for having a heart attack but you know My personal philosophy is that for localized tumors small tumors a Partial nephrectomy should be performed when technically feasible And there's currently no strong evidence that nephrons bearing preserves cardiovascular health Okay, what about lymph node dissections? So this is a cartoon that we drew for a publication a number of years ago And it was based on an anatomy text that was Published almost a hundred years ago So there was a time when you could do a PhD by doing Caterpheric dissections and studying anatomy and All the all our knowledge about these kinds of anatomy come back Come from studies done 50 to 100 years ago And it shows you where the lymphatics drain from the kidneys and what's interesting about the kidney is There's no simple Lymph node packet that drains the kidney So if you have breast cancer, you know where the lymph nodes are that drain the breast You have colon cancer, you know where those lymph nodes are and kidney Kidney if you develop a tumor that lymph nodes the tumor can go to the same side the opposite side It can go way up here. It can come way down here. So it does make Tracking the tumor in the lymphatics a little bit difficult, but What we did show a number of years ago is if you do a lymph node dissection you're gonna find more Lymph positive lymph nodes. So here we did 50 nephrectomies without a node dissection here We compared it to 50 that did have a node dissection And although the CAT scan before surgery didn't didn't show any enlarged nodes by doing a node dissection We found that almost 10% of the patients actually had disease in their nodes. So At this point what we can say is that a node dissection definitely helps you stage the disease You know in other words figure out where the disease is and then that can help guide Treatment and that's probably the most important role of a lymph node dissection and we do a routinely for High-risk large tumors that pose a risk of spread to the nodes as both Dr. Hoffman and dr. Figlin had mentioned the landscape for treating Advanced kidney cancer has dramatically changed 15 years ago when I was First starting out in kidney cancer. There were only two treatments for renal cell For metastatic disease now we have a large number of additional options so when you have disease treatments that are available and Effective in the advanced setting the next question is can you use them early on? Earlier in the disease course and can you make the treatment even more effective in that set by using it in that setting and so That brings us to adjuvant therapy so adjuvant therapy is used for patients who have Potentially curative disease but who remain at high risk for recurrence and so you give the therapy to try to prevent the cancer from coming back and This is a largest kidney cancer trial ever conducted with over a thousand patients and it it's called the assure study and it took patients with metastatic localized or non metastatic disease and They had to be at high risk for recurrence and there was a series of eligibility criteria And they were randomly assigned to Sunitinib Soraphanib or placebo and this study has completed enrollment in in other words all the patients have been accrued and now They're being followed for recurrence to see if the drug seems to be effective and What's exciting is we don't currently have any effective adjuvant therapies and this is the largest study Adjuvant therapy trial ever conducted And the results should be available By the middle of this year at the ASCO meeting There are a number of other adjuvant therapy trials I'll just mention So in this study there Soraphanib is being studied, but they're comparing three years of the drug to one year in This study Sunitinib is being studied, but it's being studied in a higher risk group than the previous trial. I mentioned this is a study That's examining a drug cut Pozaphanib and we participated in the study and This study is currently open at Cedars, and it's looking at the drug Everlymus also in the adjuvant setting now Another way to give drug for high-risk patients is to give it before surgery the term we use is neo adjuvant therapy One advantage of neo adjuvant therapy is that it can take a tumor and shrink it before surgery So here's a tumor We gave this patient Sunitinib and after three month three months But the CT was after two months that the tumor shrinks And this is a tumor that would have required the entire kidney to be removed and but by shrinking the tumor We were able to do a partial nephrectomy do it laparoscopically and here's the kidney right after surgery There's a little bit of bleeding, but the tumor is clearly gone And so we can downstage the tumor and then potentially Do a partial or a radical nephrectomy may have been initially required So I'm just to summarize what I've told you so far. There are no proven adjuvant or neo adjuvant therapies There are a large number of active agents available for metastatic kidney cancer That's being tested in the adjuvant setting You know we feel that high-risk patients should be referred for clinical trials and then at this time there are no large Neo adjuvant trials being conducted yet, but it would be exciting to see those in the near future Now a brief some comments about biomarkers So this is the flow of Molecular information inside a cell so if you have DNA which is the blueprint gets turned into RNA which then gets turned into protein and proteins are the The components within a cell that make a cell function and eventually the proteins are broken down and Metabolized and removed from the body Now the DNA was sequenced for one human being At a very high cost the human genome project Sequenced the genome of one individual from Buffalo, New York, and it cost two point seven billion dollars To to generate that sequence in 2008 There was a study that published a sequence for one tumor And the corresponding normal cell from the same individual so two sequences for seven hundred thousand dollars 2011 The complete genome cost five thousand dollars and took two weeks to generate and now We're at a point where a thousand dollars in a single day will generate the entire genome so clearly Technology is advancing Very quickly, and we're entering an exciting era of molecular and genomic medicine the TCGA is a government Funded and or and sponsored organization and what they're doing is they're taking multiple tumors And sequencing them so not only the sequence You're not getting the sequence of one individual but multiple individuals and and their tumors And this is a study that I had hundreds of kidney cancers and it has led to a led to Incredible insights in our understanding of kidney cancer so with biomarkers the technology is advancing at a mind-boggling pace What is Limiting us from applying this to patients. It's not the technology But the availability of tumor samples and understanding what that Genetic information means for any given individual so Understanding that that's where the limitation is one of the projects that we work on in our group is Looking at tissue from large data sets So this is a study that led to the FDA approval of a vast and for kidney cancer And it's the first study that required tissue submission. It's amazing that we've done a lot of trials But mandatory tissue submission is a relatively new New thing and you can see what happened in the study 732 patients are randomized and the study said if you go if you want to go on the study You have to submit your tissue to the sponsoring organization, which was CALGB and but you know to be we didn't Make patients submit the tissue before they could go on treatment because they could go on treatment with the understanding that the tissue was eventually going to come and We only got tissue from 395 Patients and I guess this is just the reality of doing these kinds of studies And it's it's an important piece of information when we're trying to plan future studies and how many samples we can expect and By the time when we actually looked at the tissue sometimes it wasn't the tissue We were looking for some of them failed quality control and so of the 732 patients on the study. We were actually able to look at only 324 but that's that's still important We also consider the heterogeneity of tumors So the tumors are not Composed of the same cell depending on where you sample the tumor looks different molecularly and even under a microscope so We we accounted for that in coming up with our genes and and Signatures for predicting patients prognosis and here are some pictures So these are each square is a single gene and it shows you based on whether the gene is high or low Your survival curve is different and so these are genes that are Prognostic and that could predict survival for patients with advanced kidney cancer and The AUC is a number that really tells you how How well it functions as a prognostic gene if you look at clinical criteria just What we currently use the AUC is point six So this is a scale that goes from point five to one higher It is the better and you can see that the molecular signature is better than the clinical Criteria and if you use them together you get the highest AUC of all and what's really exciting is That we're finding Markers that not only predicts survival but do something like this So this is a little hard for you to see but what it's showing is that if this marker is high It predicts survival to interfere it says that you're going to respond well to interfere on if it's low It says you're going to respond well to interfere on in a vast in so It's not simply predicting survival but telling you That survival is going to be good by with one treatment versus another treatment And so this is the kind of marker that's going to help us Predict treatment and allow patients to maximize their survival so this is this is the acknowledgement for the pay for the Scientist who have collaborated and worked with us on this project and from Cedar Sinai These are members of our lab and Bob figlands an important collaborator we have collaborators at a number of additional sites on this study and I'll take some questions if we have time So young I think we'll wait until the panel discussion. Thank you