 and you know first give a very brief introduction this is going to be a very basic overview of kidney cancer and then we'll get into more details. So here is a picture of the kidney and you know the important thing to point out is that this is the renal cortex but you can see that there are other malignancies that can happen in the kidney too. So I put in renal pelvis is a ureothelial cancer so that's very confusing to a lot of patients where they actually have a bladder type of lining so in the center is where urine is made so as I point out here this is called the renal pelvis and this is where urine is made it comes down the urine tube called the ureter which is then connected to the bladder so you can get when there's cancer in this lining it's typically more a urinary type of cancer and again the kidney is removed for it but it's not really kidney cancer so true kidney cancers that we are going to be spending time talking about today are those cancers that occur here in the cortex. Then there are other type of tumors that can happen in the kidney too there is lymphomas there are sarcomas but our group today we are going to focus on true kidney cancers. So what's the incident so this is this is the 2013 estimate of new cancers both in men and women and as you can see kidney cancer features it's not very common so compared to cancers like prostate and breast cancer which affects 250,000 people per year kidney cancer affects about 45,000 people per year but it still features as the top cancer in men and in women. The second half is what are the deaths that happen from kidney cancer and unfortunately kidney cancer features as the top 10 causes of death from cancer in men and so there remains a lot of work to be done in trying to improve that. So what about kidney cancer at diagnosis? We'll talk a little bit about the staging of kidney cancer but overall about 50% of patients at diagnosis will have their disease confined to the kidney so we call that localised disease and a quarter of patients present with locally advanced disease so that could involve the tumor involving the renal vein the blood vessel surrounding fat and finally a third present with metastatic disease meaning that the disease has left the kidney and has spread elsewhere so this is not uncommon and it's very classic where patients go in for completely another reason altogether so you go in for abdominal pain you get a CT and they find a tumor in the kidney. Fortunately those are localised again so that represents this group of patients but there are patients who go in for to the emergency room for a cough and they find spots in the lung and that then leads to a CT scan where you then find a kidney tumor so even today a third of patients at diagnosis already have disease that spread elsewhere and that's metastatic disease. So here is the TNM staging so this is important just to keep in mind every cancer it's not just specific to kidney but this is true for every cancer that we deal with once a diagnosis is made you want to know what's the stage and this TNM basically stands T stands for tumor N stands for node and M stands for metastasis and you pick one from each of this and it give you a stage in numbers as either one two three or four so let me just walk you through the stage. So stage one T1 tumors are those that are less than seven centimeters in size and you know seven seems like a big number but for kidney cancer it's still considered stage one if you were to have a tumor that's less than seven centimeters and all confined to the kidney would be a stage one so that's T1 there is no lymph nodes and there is no metastasis and that's stage one. Stage two would be if tumors are greater than seven centimeters but they are still confined to the kidney so that makes it a T2 again no lymph nodes no metastasis and that makes it a stage two. Stage three tumors on the other hand could be whatever size it could be a six centimeter tumor but if it has involvement of lymph nodes that becomes a stage three if it involves the blood vessels such as the renal vein or the big blood vessel called inferior vena cava that makes it a stage three and then finally stage four could be any size but if there are metastasis such as disease in the lung that becomes an M1 and it automatically makes it a stage four. Now how about the classification of kidney cancer? We know that all tumors we need to look at it under the microscope and that's what the pathologist tells us as to what type of kidney cancer it is and I want to say here that today we treat all kidney cancers alike but that just goes to show how rudimentary we are in our staging and things are improving where we are now able to know that kidney cancer is not the same there are different types of kidney cancer and the most common one on when it when we look at it under the microscope is called clear cell kidney cancer that's what happens in 75 percent of kidney cancers that are removed are of the clear cell type then there are other less common categories the second most common one is called papillary and typically you'll hear pathologists and you'll hear physicians lump them together as clear cell or non-clear cell and the non-clear cell includes these subtypes they include papillary and we have two types of papillary today papillary type one and papillary type two and then there are less common types called chromophobe or oncocytoma why do these matter because we know that these different types are driven by different type of mutations so we know that the biology of the disease is not all uniform and papillary type clear cell type of kidney cancer is driven by the one hyperlinda mutation and i'm going to talk about that in my next slide and then papillary is driven more by this mutation called C met and the point that i want to make for you to take from this slide is that there are different drugs that are in development that are coming along for different cell types so in the future we hope that we will be able to do different analysis on tumors that tells us exactly what is driving an individual's tumor so that we can target drugs individually and not use this broad one drug fits all as we do today so this a little bit of background so again you know kidney cancer typically again 75 percent are clear cell prior to 2005 we call it the pre-targeted era where the most common treatment used to be interferon or immunotherapy including intraleukin two and then starting in 2005 just our understanding about the biology of this disease led to a variety of drugs which we'll touch upon in the next several hours today that led to seven approved drugs for kidney cancer in the span of about eight years and i think that list hopefully will continue and i think till we have patients cured from this disease till we have patients who remain without any evidence of disease the search will continue for new drugs so here is a progress that has been made in kidney cancer in terms of drug therapy so in 1992 was when high dose intraleukin two was approved and i'm going to show you a little bit on subsequent slides about what the effectiveness of this drug is but typically interleukin two was approved in 1992 and has not been widely used because it's not the right drug for every patient but it's certainly been around and we have learned how to use that drug well and then starting in 2005 you can see that we've had a variety of new drugs the first approved targeted drug which affects the VEGF pathway was Surafinib and then in 2006 we had a drug called Sunitinib that was approved in 2007 there was a drug called Temserolimus which is a new class of drugs called mTOR inhibitors and then in 2008 there was an intravenous drug called Bevacissimab or Avastin which was approved for kidney cancer in combination with interferon and then 2009 there was an oral mTOR inhibitor called Everolimus and 2010 Pezopinib and in 2012 Axitinib so it's a great way to have all these drugs available to patients and I think one of the things that's remarkable in kidney cancer is that a given patient could get benefit from all of these drugs at various stages of their disease so I think that's perhaps the most encouraging news that having these seven drugs that we hope that every patient gets benefit from each of these drugs when they need it so here is just a brief background about the science behind all of this drug development so the key in kidney cancer is this protein called VHL so patients who have an hereditary or an familial acquiring of this VHL abnormality are predisposed to developing kidney cancer and they have not just so if you have this VHL syndrome you not only get kidney cancers but you also have other cancers such as tumors of the brain there are liver tumors that happen with it so the VHL syndrome is an abnormality of this VHL gene and people who have that have predilection for kidney cancers and variety of other cancers too but what we have learned is that even people who don't have this genetic predisposition in regular kidney cancers this VHL protein is abnormal and it's mutated so what happens when you have this abnormal mutation so here on the left is what normally happens to VHL so here is the normal VHL protein it combines with this protein called hydroxyproline it's an amino acid and it binds to this HIF1 alpha and then after that binding happens it normally gets broken down by this ubiquitin and it gets degraded that's the normal process that happens now if you have an abnormal VHL as happens in kidney cancer you can see that this binding does not happen okay so this HIF1 alpha just accumulates and it cannot get broken down and so there is an accumulation of this HIF1 and the consequence of increase in HIF1 are all these hypoxia inducible genes such as VEGF, PDGF so it was really this discovery that led to drugs that people started wondering okay if there are drugs that can block VEGF can we then make a difference in kidney cancer if there are drugs that block this PDGF would that make a difference so really it was understanding this pathway that led to the development of all of these new drugs so here is an example of the VEGF pathway which we now know in kidney cancer is really the key in some of the drugs that we use so this VEGF is called the ligand and it can be blocked in many different ways okay there are antibodies that can prevent this binding so that's what a vastness it's an anti-VEGF antibody or you can just prevent this this this VEGF is the ligand it has to bind to this receptor called VEGF-R and once that binding happens the tumor then can proliferate and can grow so you can prevent this either by an antibody up here or you can prevent this VEGF from binding to the receptor and that's what these small drugs such as sunitinib, soraphinib and other drugs do so that's the VEGF inhibitors and you can see up here we have drugs such as sunitinib, soraphinib, axitinib and posopinib all working by blocking this VEGF inhibitor and then we also have the other class of drugs which are called mTOR inhibitors and you can see they all complexly interact with each other and we have two drugs everolimus and temsirolimus so in summary then the medical therapy for kidney cancer in 2014 really includes three classes of drugs you have immunotherapy which includes intralukin-2 and interferon and you'll hear as the day goes by that we are hopeful for the future that this list is going to be expanding and there are many new drugs in development and very close to coming to patient care in the future and then these are the VEGF inhibitors they include sunitinib, soraphinib, posopinib and axitinib and bevacissimab which is the intravenous form and then the third class of drugs are the mTOR inhibitors everolimus and temsirolimus so this is a brief overview just so that you're introduced to what you're going to hear in the day today so with that I'm just going to share with you the agenda for today I've just done my little welcome spiel unfortunately the next person which is the CEO of kidney cancer association he couldn't be here today but he shared a slide which I'll show you in a minute and then I'm going to then give you again maybe I see Ben up here just for the chronology of things it might be a good idea for Dr. Chung to talk a little bit on local therapy because that's what really happens you have tumors confined to the kidney and we want to talk about the surgical management and then I'll come back and talk about the medical treatment just to give you an overview of each of these drugs and some of the important questions that we have learned over the last decade with all of these new drugs then we are going to have Dr. Horstack so she's a medical oncologist who's now at Kaiser she's going to come and talk to us about immunotherapy and I think that's really the most exciting area in the last year that we have learned about some of the new drugs so she's going to give us an update and then I'm hoping that Dr. Louis John-Louis he's on call today but he said he would come by so we may have to have some flexibility in the agenda today so he's going to come and he's a radiologist here at Stanford he's going to show us some of the novel ways by which radiologists are able to do local therapy and he's going to use liver directed therapy as an example for how radiologists can help us treat some of these tumors that you don't need a full systemic treatment but may be confined just to the liver we are then going to have some time for panel discussion again as I said this meeting is for you so I really want to encourage all of you to participate and feel that your questions have been answered so that's a good time for discussion we are going to break out for lunch and during lunch we are going to have one of our social workers her name is Jordan Chavez who's going to help all of us interact and perhaps if you feel comfortable telling your story so that the rest of us can hear about it Jordan is going to help facilitate that at lunch and then in the afternoon we are going to have Dr. Leppert who's one of our urologists he's participated in this conference many times as well he's going to talk about some fluorescein imaging that he is engaged with we are then going to have again an overview from one of our radiologists in nuclear medicine Dr. Eric Mitra who's going to just give us what is done for imaging how best can we look at different scans for kidney cancer and how best imaging is done one of our junior colleagues her name is Alice Fan she's a medical oncologist who works with us here she's going to come in the afternoon and talk about how do we know that the treatment that you're getting is working so she is engaged in some very novel ways in which we can help determine those for for our patients and finally we'll hear about the side effects from some of these drugs and how best to manage those side effects so we have invited Melissa Vietori she used to be a nurse practitioner here at Stanford who's now at UCSF so she's going to come in the afternoon and help give us a talk and with that we'll close the day so we have a very good agenda for you and again I want to thank all of you for coming here and sharing your day with us today