 My name is Sandy Srinivas, I'm a medical oncologist at Stanford, and I specialize in taking care of patients with kidney cancer. And I'd like to welcome all of you and thank you all for coming in today. I'm going to have a brief introduction just to give you, most of it may be what you know, but we are hoping that the day today will give you some new information. I love you to share your story with people who have similar stories like you do, and more important, share medical information about what's new, what you've been through, and look at what the future holds in terms of promise and clinical trials and new drug development that we all want to continue to work on in trying to improve the outcome for patients with kidney cancer. So again, thank you all for taking your time on a Saturday to come and share your day with us. So I'm going to start off by just giving you a very brief background just so that it puts all what we hear today in context. So this is a picture of the kidney. So I'm just going to use this, I think I can use. Yes. It doesn't work? Oh, does that work? Okay. How does it work? Oh, I see, okay. That's fine. Thank you. So here is a picture of the kidney. And what I want to point out here is that not all tumors that start in the kidney are really kidney cancer. So the majority of kidney cancers are those that arise in the renal cortex. Okay. This is called the renal pelvis, which is where urine is made. It's the lining of the urinary system and it's similar to a cancer that starts in the kidney. So it's very important to really, when we look at a picture, especially of a tumor that arises, let's say, right bang in the center, we really have to do a biopsy to make sure that this is kidney cancer or is it the urinary type of cancer. Okay. So the most common ones is if it's in the cortex, that's what is called a renal cell carcinoma, which is what we are going to be spending our time talking today. Then there are tumors in the renal pelvis. These are more urinary type of tumors. And then there are other tumors that can arise in other parts of our body, including lymphomas. So lymphoma is usually a tumor that arises in lymph nodes, but it can occasionally involve the kidney as well. And then finally, there are some generalized tumors like sarcomas. Those can happen in the kidney, but they are very, very rare. So it's really important for us when we talk about kidney cancer to know exactly which kind are we talking about. Here is the estimated statistics for the year 2013. And I think this is for both men and women. And I think I want to just point out that kidney cancer in terms of the top 10 cancers features in both men and women as one of the top cancers that affect us. Fortunately, if you look at the deaths from kidney cancer, it's a little lower down. But we are hoping to improve that with time where we are able to diagnose this disease early, make a treatment so that there are far fewer deaths from kidney cancer today. Here is a little bit as people talk through the day about stage and what this means. The majority of people fortunately who are diagnosed with kidney cancer have localized disease. And that represents about really half of the patients. And today it's very common that if you go in with abdominal pain, for instance, you get a CT scan and they note an incidental kidney mass. So a majority of people are diagnosed that way. And those tumors are highly curable as you'll hear in our later talks about localized kidney cancer. Then there is a quarter of patients who end up having more advanced disease than just kidney, than tumor, a small tumor in the kidney. It can involve the blood vessels, the renal vein. It can involve the large blood vessels that run across our body called the inferior vena cava. And those are still surgically removed, but they are considered to be a little bit more locally advanced. And finally a third of patients today present with metastatic disease as their first site. The kidney is in an anatomic location where it can just grow without really having any symptoms. So many patients are fortunate if they end up having blood in their urine, because that's something you don't ignore and you bring it to medical attention and you get a scan done and a diagnosis of kidney cancer is made. But for a majority of people just because of the location of where this organ is, it can grow. And many patients just present for completely recent outside of the tumor in the kidney. For instance, it's not uncommon to go to the emergency room with a cough or a chest pain and find a spot in the lung. And then they go back and look and they find that there is a tumor in the kidney. So here is a quick staging guidelines in terms of what we talk about. What is stage one and what's stage four? Obviously stage one are small tumors that are less than seven centimeters and they are confined to the kidney. That's stage one. Stage two is tumors that are still confined to the kidney, but they are larger than seven centimeters. That's stage two. The minute you have involvement of lymph nodes or if there is involvement of these big blood vessels, that's called stage three, which is what we call as locally advanced kidney cancer. And then finally stage four are when we have disease outside of the kidney and its vicinity, either in the neck, in the chest, or in the liver or bone. That would be considered stage four. So I want to just briefly spend a minute talking about when we remove the kidney or when we do a biopsy. They all look different under the microscope, so it's important to know what the histology of these kidney cancers are. The majority of the tumors are what we call as clear cell kidney cancer. That's what happens in 75% of patients. And we'll talk a little bit about what the significance of this and what we have learned about this disease over the last decade. But the majority of patients with kidney cancer, 75% of them end up being the clear cell type. Then there are some other rare types. So there is the second most common one called the papillary, and that represents about 15% of kidney cancers. They look different under the microscope. They have a different biology that's driving them. Even today in 2013, we are slowly beginning to do our treatments that are different for clear cell compared to non-clear cell. And I think in the next five to ten years, it's very clear that we will be having more buckets than just this, where we will be able to identify different cell types and what's driving individual cancers and how best to treat them. But this is the classification today with clear cell, the second most common one being the papillary, and then there are rarer types which have a different behavior. One is called chromophobe, and the other one is an oncocytoma. Through the day we are going to be talking about different treatments, whether it's surgical treatments, whether it's medical treatments, and then some of the clinical trials and new drugs. But just by way of background, kidney cancer really affects close to 65,000 people per year, and again 75% of those will be clear cell. And prior to 2005, the standard treatment for patients with metastatic disease used to be immunotherapy. And immunotherapy was really only applicable for a small fraction of patients. It included two drugs, one was called interferon, which you'll hear about today, and a second drug called interleukin-2. And interleukin-2 was associated with significant side effects, so it was really applicable to a very small fraction of patients. And then in 2005, dramatically, there's been enormous changes in the way we treat kidney cancer. And since 2005, as you know, we now have seven approved drugs to treat this disease, and it's all stemmed from our understanding the biology of this disease better in the last decade. So here is a slide that I like to show showing you where we started and where we are today. So 1992 was when high dose interleukin-2 was approved. And again, you know, it's been, even though it's been around, it has been applicable to a very small fraction of patients. But high dose interleukin-2, as you'll hear from Dr. Minor today, is one of the treatments that really results in long-term cures for patients. And there's been a lot of research looking at who that small group of patients would be, so that we can select those patients better and give them the best drug, and we are not there yet. And then in 2005, since 2005, you can see that there's been almost every year we have had a new drug. So Surafinib, Sunitinib, Pozopinib. These are all in a class called VEGF, TKI's. We'll talk about that in a minute. And then there are two drugs called Temsirolimus and Everolimus, which are MTOR inhibitors. So I think, you know, the point of this slide is just to show you that there's been enormous progress made in the last seven to eight years. And I think there's more new pathways and new drugs coming. So I want to just leave some hope that there are new drugs with better improvements in the way we treat this disease. So a little bit about biology, because this is what the whole drug development and where we are today stemmed from. And it comes from understanding what drives kidney cancer. So we know that there is this protein called one-hipple lindar protein. You'll hear a lot about it. It's called the VHL protein. And there are some patients and families who have this abnormality in this VHL gene, and they are predisposed not just to developing kidney cancer, but can get a variety of other cancers. But it turns out that you don't need to have a genetic predisposition. Even patients who get kidney cancer, a majority of them have an abnormality in this protein called VHL. So I just want to show you this little cartoon to sort of explain what happens. So in this side is what normally happens. So we have this VHL protein. It binds to this HIF1 alpha through this hydroxyproline. And after it is bound, it then gets broken down through this process. And then this HIF1 gets degraded in our body. This is what normally has to happen. If there are abnormalities in this HIF protein, as can happen in kidney cancer, there is an alternate pathway that happens. Look what happens here. There is ineffective binding, first of all, of this HIF2 VHL. And therefore it can get broken down. So there is an accumulation of this HIF1. What are the consequences? What happens when HIF1 gets accumulated in our body? We get a lot of abnormal genes and proteins which include VEGF and these proteins called PDGF. And just the understanding of this made a huge change in the way we started learning about kidney cancer. So in the next slide I'm going to show you now that we know that in kidney cancer there is accumulation of HIF. And there is increase in this VEGF. How can we block this VEGF? So that's what led to this entire drug development where we figured out ways by which we could block this VEGF pathway. So there are different ways in which it can be blocked. You can either block the VEGF ligand itself or this is the receptor. So the bottom line is that I want you to just take a message from this is that there are many ways by which this VEGF can be blocked. And you're going to hear about some of the drugs that we use today that are effective in blocking this VEGF pathway. So we now know that there is an interaction between VEGF and this HIF. We have already made that association in the last couple of slides. And then there is also an interaction with this other pathway called MTOR with HIF. So here are all the drugs that many of us are familiar today. So you have Sunitinib, Surafinib, Axitinib and Pazopinib all blocking the VEGF pathway. You have drugs like Temserolimus and Everolimus blocking the MTOR pathway. So we know that these drugs work over the last five years. There have been attempts at trying to combine these to see if we could make progress. And unfortunately that strategy has not been very successful. So in kidney cancer we just go with one drug after the next and have patients benefit from these. So here is my summary for where we are today in 2013. We really have three classes of compounds that are used to treat this disease. Immunotherapy is the old one that we had prior to 2005. And I want to leave you as the day goes by you're going to hear that this is really coming back. Immunotherapy has become such a big path in kidney cancer that it's definitely back again. And there are now strategies to combine immunotherapy with some of the existing drugs that we have today. So stay tuned to learn more about immunotherapy. And then there are the VEGF inhibitors and then in this class we have again Sunitinib, Surafinib, Pazopinib and Axitinib. These are all oral drugs that you take by mouth. And then there is an antibody called Bevacissimab or Avastin which is given intravenously. And then the third class of compounds is the MTOR inhibitor. One is Temsirolimus which is given intravenously. And we have an oral drug called Everolimus again in the same class. Our hope is that we will have completely another class of compounds when perhaps when we talk again in a year from now, again showing the progress that we made.