 Good morning as mentioned my name is Jean Zen one of the radiation oncologists at the University of Washington And I'm going to speak a little bit about the role of radiation and kidney cancer Many of you are probably not too familiar with radiation therapy. So starting with the very basics Most radiation treatments in the United States are generated using these machines called linear accelerators And so this is what an image of a linear accelerator looks like and basically the radiation is actually generated by this machine And it comes out of the head of the machine in something we call a gantry So the patient is lying on a treatment table like this and the whole thing feels a lot like a CT scan But basically this gantry on top can actually rotate 360 degree around and the table that the patient is on can rotate as well So you can have radiation beam angles that come from any direction There is no radioactive material anywhere in the room The only time there's radiation present is when the machine is on and the patient is getting treated So some of the common questions I get are you know, while I glow in the dark? No, you will not Am I harmful to other people? No, you are not because you are not radioactive There's been a lot of changes to radiation therapy over the past few decades the goal radiation therapy as well As I guess all cancer therapies has always been simple You want to kill the cancer cells and you want to try not to kill the patient Accomplishing that of course is much more difficult and so kind of in the beginning stages of radiation We started with very simple rectangular shaped radiation treatment fields so on the left is basically an x-ray of a patient kind of low back and pelvis and Drawn and out lines of kind of this light green and orange line Are two bones in the low back that have had cancer spread to those bones? And we are providing radiation therapy to help treat on provide pain relief and You probably it's probably hard to see but there's a red rectangle that's outlined and basically that's the shape of the radiation field It's a simple rectangle where we have one beam usually come in from the front one being coming from the back And that's how we treat that lesion the image on the right is a picture of what a whole green radiation field looks like So as mentioned previously sometimes cancers including kidney cancer can spread to the brain and if there's just one or two Spots we will try to do very focused radiation But if there's a lot of different spots then we will often just do radiation to the whole brain And we treat that which is this basically rectangular shaped field We do add blocks over here on one side because you're trying to treat the brain inside the skull and there's no reason to Treat the face But these are you know fairly simple radiation treatments and we actually still do this in our clinic today a More recent development in the past several years has been something called radio surgery or stereo tactic radiation There's a lot of different names for this depending on who's advertising it But basically the general concept is instead of kind of one or two rectangular shaped fields You're now using radiation beams that are coming from a lot of different directions They're all converging on the tumor with the help of providing a high radiation dose for the tumor and a much lower dose elsewhere So this is an example of a patient's lung x-ray with a tumor depicted in the left lung and these yellow lines showing a lot of different radiation beams coming from different directions converging on the tumor So what might that look like on a CT scan? So for example if this is a patient who has a tumor in the lungs say it's a kidney cancer That's spread with a lung nodule on the top image You basically have a little red circle showing there's a tiny tumor right there And in the middle image you're seeing a lot of yellow lines showing a lot of different radiation beams coming from every which direction All converging on the tumor and on the bottom figure your show is basically seeing these lines Representing different doses of radiation. It's a little bit like a topography map. So there's a thicker yellow line That's basically saying that's the full dose of radiation that we're giving and that's covering the tumor plus a few millimeter margin And then there's a kind of pinkish line a little bit further out that represents about 50% of the radiation dose And then there's a much fainter teal line with a lot of fingers sticking out that represents about 10% of the dose So you're basically seeing the track of the different radiation beams Converging on the tumor to provide the full dose of the tumor while falling off much lower doses of radiation as you move further away from the tumor Similarly another very common scenario that we use this for is for treating patients whose tumors have spread to the bones and the spine So the vertebral bodies and the spine so the very kind of simple Decades old way of doing it is with a rectangular shaped beam coming in from the back similar to what we saw in one of our earlier slides and Basically you have full dose tonic to the back and the icidose lines kind of fall off as you go to the front But you're basically providing a fairly high dose of radiation to this entire whole rectangular area More recently you can now use different beams of radiation So this one is actually using nine separate beams radiation coming from different directions They're all still converging on the tumor So now you're getting a much higher dose to this bone that's involved with cancer in the back And there's lower doses elsewhere in the body and the very last one is talking about something called I am RT Standing for intensity modulated radiation Meaning not only do you have radiation beams coming from different directions But the shape of the beam actually changes during treatment And what this can do compared to the other radiation techniques is you can carve kind of a concave shape So for something like the spinal cord Spine lesion where you're trying to treat the bone surrounding the spinal cord But you would ideally like to not give a lot of radiation to the spinal cord itself The something called I am RT can actually carve out a doughnut So you're actually getting a higher dose to the bone surrounding the spinal cord and a lower dose the spinal cord itself This is a kidney cancer conference. So of course we can also do this to the kidney These are three images showing axial sagittal and coronal slices Of a CT scan basically showing there's a tumor in the left kidney And we are aiming at that tumor and that red splotch is basically the full dose with a very light blue Splotch about 30% of the dose and so this is a sagittal image kind of going like this and what you're showing is This is the size of the entire kidney and we're aiming at a tumor that seems to be in the middle Third of the kidney and this is another corona slice showing that as well that this is the whole kidney And we're giving radiation to about the middle third of it One thing I will point out is for bringing the task This is we can treat with radio surgery as well But we do it with a slightly different machine and a slightly different system We have a system called the gamma knife and here You actually do have radioactive sources cobalt inside this little kind of the head of the machine here The patient is lying on the table and we attach this immobilization helmet device to them They kind of move back into this into this head of the machine and they're actually up to 201 radiation beams But we don't usually use more than eight to ten at a time depending on the location of the tumor And you're able to focus on the radiation on a brain tumor with it with accuracy of about within about a tenth of a millimeter This device unfortunately doesn't work for anything outside the body because you have to be able to go into the machine And so you can do that with the head, but you can't you know put a lung in there You can't go back in far enough And so if we're going to talk about being very precise with the radiation to perhaps within a millimeter Then you need to be very confident that you know where your tumor is when you're treating Otherwise, you're going to miss and so with the technology evolution There's also been an improvement in terms of image guidance so image guided radiation therapy What does that mean? so I think we look at an image similar to this whole brain radiation at the beginning of the time our time together and Basically if we were treating a patient with whole brain radiation Then when we treat the patient we would actually take an x-ray before we treat to make sure that we see the skull That the beam is positioned correctly and the patient is positioned correctly and then we would turn on radiation beam But what you're talking about some of these more sophisticated radiation treatment So the skull is an exception because your brain is entirely encased by bone and that's easy to see on an x-ray But if you're treating a tiny tiny nodule in the lung or the kidney or the liver You don't necessarily see that very well on an x-ray image And so now there's been evolution where before we treat for these high-dose treatments We actually do a CT scan every day on the treatment table before we turn on the radiation beam So for example, this is what a CT scan might look like that we use to plan the radiation treatment So there's a tumor in the lung right there and the older what we call combing CT That's just the name of the CT scan we get before do radiation treatment looks something like this It's not great quality, but it's at least better than an x-ray and being able to show you Oh, yes, there's a long tumor right there We can do all sorts of fancy fancy image registration things to make sure that your lining patients up properly But the newer generations of combing CTs have improved in quality So that you're not able to see things pretty well and you can make sure that you're aiming at the correct target before you turn on radiation beam Something we else we deal with in the chest as well as upper abdomen where the kidney resides is tumor motion So again, you need to see where the tumor is and need to make sure that what you're treating is not moving So for example, we live in a three-dimensional world, but in radiation oncology We talk a lot about a four DCT where the fourth dimension is time So this is an illustration of for example, if you had a tumor in the lower part of the lung The problem is that as we breathe your diaphragm moves up and down And so tumors in the lower part of the lung as well as the upper abdomen move with your respiratory motion And so this is showing an example of if you're taking in a breath Inspiration then your diaphragm moves down because your lungs are expanding and so the tumor tends to be lower down in the chest But if you exhale your lung volume is now a lot smaller and so the tumor actually moves up in the chest So for a tumor like this if you only did a scan on one phase of the breathing cycle You can actually miss this and then aimed at it You can actually miss the tumor for a good portion of the breathing cycle So there are two major ways to deal with this one is you just make the volume that you're treating bigger So that you're encompassing the entire volume of the tumor as it's moving up and down as you're breathing The other volume option is do something called respiratory gating And so what's happening is a patient is on the table and we actually put a little marker on their abdomen because you can Trek respiration based on sort of the abdominal wall motion You have a little camera that's tracking it The patient is wearing a pair of fancy glasses and they can actually see their breathing cycle kind of go up and down As their abdominal wall goes up and down and we program the computer so that the radiation beam only comes on for a portion of the breathing cycle So for the tumor that we were just looking at for example We can say well We are only going to treat this when the tumor is over here inside the circle and not when it's out here outside of the circle And so as we're tracking the patient's breathing between inspiration and respiration with this squiggly line here We can actually program the computer so that the radiation beam only comes on so you're you don't Have to treat a large volume to get the whole tumor as it's moving through the respiratory cycle But you're not you're also not missing the tumor for part of your treatment time And so I thought you know so that was kind of a reveal of a lot of our toys But I thought I would actually mention some of the relationship to sort of a relationship between radiation and renal tumors a lot Of you are probably not very familiar with radiation unlike certainly what dr. Tycote and dr. Gore does and part of that is because radiation has not been used very much in kidney cancer treatment There's been a lot of debate But most people would agree that renal cell tumor cells for whatever reason are a little bit radial resistant Meaning it takes a slightly higher dose of radiation to kill a renal tumor than many other kinds of cancers that are out there Surgery has been the standard treatment for localized renal cell cancers But we know that sometimes cancers can still come back after surgery and so for decades We have tried adding conventional radiation to surgery by conventional I mean unlike radio surgery where you get a very few treatments Very high dose per treatment like three to five treatments Conventional radiation you get treated with a low dose of radiation every day Monday through Friday And this goes on for several weeks five to six weeks usually We've tried adding this kind of radiation to either before the surgery or after the radio after the surgery In order to for in hope of decreasing local recurrence There's been multiple randomized trials done about this and unfortunately it's not clear that I actually helped and Unfortunately, the treatment can also be quite toxic because we're treating a fairly large area of the body Not only do you want to get the kidney with its tumor? You're trying to get all the lymph nodes in the area that could have tumor spread and so we really do not do this However in the more recent years with technology evolution There's been more interest in trying to do this radio surgery so very high dose per treatment very few treatments somewhere between one to five and There's a lot of very right now The data is still fairly new and so most of the data consists of very small patient series Meaning someone saying well, we treated 20 patients with this and this is how they did this is probably a slightly bigger study That was published in the last year looking at 40 patients who had a total of 45 Surrogically untreatable renal tumors and by surgically untreatable usually it means the patients are not in good enough medical shape to undergo and Fractomy and Basically what they felt what they did was they gave 25 gray of radiation You don't have to know what that means other than gray is just what we used to measure radiation dose But 25 gray in one is a pretty hefty radiation dose And basically what they're trying to show here is the patient had a tumor in the right kidney on an image like this left Is right right is left and each one of these blue lines represents a beam direction for the radiation So lots of directions for the radiation beam converging on the tumor in the right kidney And these three images basically just show coronal sagittal and I'm sorry axial sagittal and coronal images With the radiation dose line distributions look like with the red line being the areas that they wanted to treat and green line being the full dose of radiation and then the lower doses as you move further away and At a medium follow-up of about 28 months, so a little over two years the average tumor size they treat it was about 42 ml most of us don't know what that means so it's about the size of a golf ball and 39 of the 45 tumors that were treated were in remission meaning they were smaller and then they did not get any bigger 19 tumors disappeared. So what does that look like? So this is a sample image of basically a left kidney tumor this black area is basically the tumor this white area is normal kidney and This is the tumor that was treated with radiation and about a year later. There's still something there We don't know for sure what it is. It could be scar tissue. It could be live cancer cells The only way to know for sure would be to do a biopsy to remove it But basically patients are then continually monitored with imaging and if it's smaller great or it doesn't grow But if it's growing then we count that as progressive disease What were the overall control rates these are all very well selected kind of patient populations So overall they were just trying to say that progressions free survival and overall survival at a time point of like two years is fairly reasonable about 80 to 90 percent The treatment was fairly well tolerated a little bit of kind of skin irritation dermatitis from radiation a little bit of feeling tired There's some nausea because there's usually a lot of bowel around the kidney and stomach So there can be some nausea so that's out of 40 patients total and then for these patients who all had fairly normal kidney function to begin with The it just shows that the radiation at least did not kill the kidney function They still had relatively normal kidney function after the radiation treatment The authors concluded and I think it was a fair statement that in very carefully and well selected patients The short-term safety and efficacy of radio surgery the kidney tumors seem encouraging But again these are very short follow-up treatments the results seem similar Not necessarily better than other kinds of a blade of techniques that are out there And it's you will need further study with bigger patient populations and longer follow-up to see what's really the long-term efficacy of these treatments Similarly in patients, you know, I think as dr. Ty Cote mentioned radiation we tend to see patients a lot more for kidney cancer who have already metastasized So we certainly do radio surgery to sites of metastatic disease as well And similarly there's a lot of kind of small patient series out there showing what the efficacy is This is a particular series looking at 50 patients who have metastatic renal cell carcinoma and eight patients with inoperable primary renal cell carcinoma They actually treated 152 tumors total out of these patients and so most patients were getting treated to about three to four spots with radiation because I've metastatic cancer the regimens were not quite as aggressive as 25 times one 25 gray times one treatment, but they're fairly aggressive as well. It's usually somewhere between three or four treatments and The vast majority of these patients were treated to the lungs is that tends to be a spot that the renal Kidney cancer spreads to quite a bit with other sites spread out through the body as well including media staining Other kidney adrenal gland liver, etc. and bone of course In terms of local control, I think you know with radiation if we give a high enough dose of radiation We can kill anything so local control is pretty good But the sobering fact is unfortunately these are patients with metastatic cancer and they develop new metastatic cancer spots during follow-up And so it's always very sobering that you know, there are limitations to what we can and cannot do in terms of side effects Again, these are fairly well tolerated out of the 58 patients that were treated grade one side effects They're usually pretty mild there you may notice them, but you're not terribly bothered by them grade two They're starting to become more bothersome But they usually are relatively easy to manage with say a new medication or something like that Grade three that's starting to be more serious because you usually have to intervene like do some kind of procedure Grade four is usually something that requires hospitalization, but overall it was reasonably well tolerated And I think the last portion I'll talk about is you know radiation We've always considered ourselves to be a local therapy meaning it works where we point the beam it doesn't work elsewhere, but we are also very excited about all the developments in immunotherapy and We are also actively trying to figure out what can we do to partner with it because I think dr Tech Cody presented very exciting data But the problem is it's not the response rates overall are not high and we certainly like to see it higher And so what we know is by the time someone has a tumor that's large enough to be seen on a scan It's probably figured out some way of evading the immune system Otherwise you would never have known that it was there and so usually a lot of these tumors They're in some kind of immunosuppressive environment, which is why giving a drug that kind of in Kansas the immune response works So for radiation what we think happens sometimes is there's a tumor we zap it with radiation It dies and in the process of dying it releases a lot of protein called antigen that ordinarily would not be seen and If your tumor is just sitting in a very immunosuppressive environment Then it can release all the antigen at once your immune system still won't respond because they're being suppressed But if you're using radiation and something like one of the immuno checkpoint inhibitors together Then maybe they can help boost each other. So it's almost like having a vaccine And so the this has been looked at for the longest period of time in melanoma And this is a case study report that was published in a very prestigious medical journal in 2011 New England Journal of Medicine and it was actually just a case report of one patient with melanoma that was metastatic and This patient was on the ipuloma mask. It's the one of the kind of CTLA for Immunotherapy agents and what this patient had was multiple sites of disease from the melanoma So there was a spot on the right side of the spine up there that the white arrow is trying to point to There were some lymph nodes in the lung There is a spot in the liver and at the time the patient's spleen was perfectly clean So this is August of 2009 the patient is on ipuloma mask and by November 2010 There's cancer progression in all these spots. So the spot in the back was a little bigger The lymph nodes in me to sign them were a little bigger The liver spot was a little bigger and now there are multiple spots that are visible in the spleen At this point the patient because of pain in the back received radiation radio surgery to the tumor that was in the back So that's what this bottom left figure is basically they received 9.5 grade for three treatments focused on that tumor in the back and They continued on ipuloma after in this whole time and what they saw was a month after radiation treatment Everything still looks about the same nothing's changed yet because it takes a while to see response About three months after that the tumor in the back is a lot smaller not surprising We treated it with a fairly high dose of radiation But what was completely surprising was that even though they're on the same drug ipuloma Map that they were previously progressing through the other spots of cancer were responding as well So the lymph nodes in the media stymum the liver spot all the spots in the spleen And this remains sustained over about the nine month period that the case report was reporting And so there's a lot of excitement about the possible combination of radiation and using that with these checkpoint inhibitors to prime the immune system So right now at the University of Washington We actually have a clinical trial for patients with metastatic melanoma and radiation and we're in development with our colleagues to Possibly open up a similar trial in patients with metastatic Renal cell carcinoma as well with basically you don't have to look at all the details of this trial schema But what we would be proposing would be that patients are on this nevola map that we heard quite a bit about from dr. Ty Coney They also get another drug It's a pill called now finivir that helps to prime the immune system as well as three doses of radiation to a particular tumor somewhere in the body and Then we kind of monitor response not only to the tumor that we treated but also elsewhere as well So because as I said the medical community were very excited about immunotherapy But there's a lot of work underway to try to figure out. How do we make everyone? Every patient we treat one of those kind of miracle responders that you see on the news So I think that's probably the entirety of my talk and I think the only other thing I was going to say that I think I got a hint of from dr. Gors talk as well as dr. Ty Coney it's not just about the technology It's about knowing how to use it so and sometimes knowing when is the right time to not use it I think that's all I have to say. Thank you Last thing you were talking about the upcoming study on the immunorab Were you talking about melanoma patients or kidney cancer? So for that particular study, we would expand it to include patients with melanoma kidney cancers and long so those are three cancers where the Immunotherapy the nevola map are currently considered to be standard of care