 Last speaker this morning's program, Dr. Jing Zhang from our radiation oncology department. We'll be talking about advances in radiation therapy for kidney cancer. That will bring us to the end of our morning session. I know we're a little bit over, but any of the speakers that can stay, I'd ask the morning faculty to come down if people have questions. We'll turn the rest of you loose for our lunch break. So if we finish up about 12.15, a panel can try and stay until about 12.30. Why don't we plan to end lunch and we can be in at one o'clock. Thank you. I am mindful that I stand between you and lunch, so I'll try to talk fast and I'm happy to stay for questions. As Dr. Ty Cote introduced, my name is Jing Zhang. I'm a radiation oncologist working at the University of Washington, Seattle Cancer Care Alliance as well as our Proton Therapy Center. I think most people are not too familiar with radiation if you haven't been through the process yourself or have a family, someone close to you who's gone through it. These are some of the most basic questions I get from patients about radiation treatment, which is radiation comes from a machine. The way that you're treated actually feels a lot like getting a CT scan. You're basically lying on your back on this table and there are going to be therapists and technologists kind of moving all around you in the room and there's a machine that's going to move around you as well. There's no radioactive material anywhere in the room. The only time there's radiation is when you're in the room by yourself and the machine is on. This is a little different from a type of radiation called brachytherapy where they're actually implanting radioactive material into you. It's used most often in prostate cancer but it's pretty much never used for kidney cancer treatment. You don't see the radiation, you don't feel the radiation just like when you're getting an x-ray or a CT scan. You don't even know when the machine is on except for this instead of scanning a whole section of your body we're aiming at one particular, hopefully small section of your body. The goal of radiation therapy probably like all my other colleagues is always to kill cancer cells and try not to kill too many of the normal cells that are around in that region. Decades ago, and we still do this as well which is the simplest kind of radiation which we treat people with these rectangular shaped treatment fields. And so for example on the left here is an x-ray of the pelvis. This is a patient who had a cancer, for example kidney cancer that's gone to a couple spots in their spine. So a lumbar vertebral body as well as their sacral and we're basically treating them with this rectangular radiation field to try to treat the cancer in those bones that are most likely causing pain or causing nerve damage by compressing some of the nerves in that area. This is a patient who had cancer that's spread to their brain and so we're actually giving whole brain radiation in this particular incidence and you're basically seeing the shape of the radiation field here. This part is blocked so that there's no point to needlessly treat the eye or the mouth or anything like that where we're aiming to treat the whole brain with radiation. Over the past few decades there's been a lot of advancements in radiation technology so you're hearing more about things like radio surgery. Cyber knife for example is a brand that a lot of people have heard of. It's a type of radio surgery made by a particular company but basically the goal of this is instead of treating you with rectangular based radiation fields there's a lot of different radiation beams that are all coming from different directions so that they all converge on a tumor so that you're getting a high dose of the tumor but lower dose elsewhere in the body. So for example if you had a tumor this is the CT scan of the lung a cross section of your lung and this little red circle is outlining a tumor in the lung that's been growing so for example it's spread from the kidney to the lung and we want to kill this tumor with radiation and so what we do is we give this treatment called radio surgery or cyber knife or SPRT and you just have a lot of different beams of radiation all little beams of radiation coming from different directions they're all converging on this lung tumor so that the different colored lines are representing kind of higher and higher doses of radiation so you get a full dose of radiation to the lung tumor and then as you move away from the lung tumor the radiation dose falls out very quickly to elsewhere all around. I think a lot of people are also starting to ask me more and more about proton therapy because they're starting to hear about it what I tell patients is proton radiation it's still a type of radiation it's a FDA approved technology it delivers radiation to the tumor and theoretically it may be able to reduce radiation to some of the surrounding normal tissue and it's useful sometimes, not all times and I also say it's a tool for the radiation oncologist meaning you know just like SPRT radio surgery, cyber knife are tools and it's only useful when you need radiation if you don't need radiation then you don't need proton therapy so the major difference I won't go too much into the physics but the major difference between proton radiation and regular radiation regular radiation is represented here by this red curve called photon or x-ray radiation there are different names for it but I'll just call it regular radiation and what this is representing is depth into your body versus the relative dose of the radiation so what happens with regular radiation is it goes into your body it reaches its maximum dose damage at some point, some depth in your body and then it actually exits out your body at some point so it travels through and through and so that's why earlier when I showed the figure of the lung radiation you have a lot of different beams that come from different directions as well but since you're converging on a particular point the dose is high at that point and then becomes much lower as you move away from it with proton radiation the major difference is it goes into your body it's represented by this purple curve here it goes into your body reaches a certain calculated depth and then stops and there's no radiation coming out the other side and so unfortunately most of the time we're not treating a 1mm large tumor you're treating a much larger tumor for centimeters and so in order to get that kind of depth coverage you have a lot of these little purple curves that will eventually add up to this green curve so when is it a good idea to use proton radiation usually it's because you're trying to treat a particular tumor to a high dose but there's a critical organ next to it that you don't want to give quite as high of a dose to we treat a lot of children at our proton center because in them they typically have decades more to live so you worry about other side effects that are long term like cancer or radiation or development or growth delays or organ damage we also do this a lot when we're trying to re-treat the same area because your body has a lifetime memory for radiation so it's hard to treat the same area over and over multiple times so usually when we talk about proton radiation the poster image that we're talking about is treating pediatric cranial spinal radiation there are certain kinds of children with brain tumors where their cancer is actually likely to spread from the brain all down the fluid to the entire spine so they end up needing radiation to not only their brain but their entire spine as well the cure rates for these kinds of tumors are actually relatively high overall it's about 80% cure rate meaning 80% of these children are going to live for several decades after treatment so when you treat them with regular radiation because the radiation goes in from the back and comes out from the front you're not only treating the spine but as these cross sectional images show you're also treating everything in front of the spine whereas with proton radiation the radiation goes in, covers the spinal cord and then stops and so this is probably the one scenario where you have the most amount of advantage from treating with proton radiation versus regular radiation but there are also scenarios in the abdomen so for example, again I think Dr. Taikoti discussed that there is currently no evidence to give radiation after surgery for kidney cancer if it's localized but there are certain kinds of children that have kidney cancer, specifically Wilms tumor where it's actually standard for them to get radiation to the entire post-opterative bed after they have their kidney removed for their kidney cancer and so if you imagine if you're treating that whole area on a scan like this if you use regular radiation and you're kind of going front to back then not only are you treating where the kidney used to be which is kind of back here but you're also treating a lot of liver needlessly for no benefit whereas if you treat with something like proton radiation you go in from the back treat the entire post-operative bed and not have to give excess radiation to the liver in the front similarly, this is a patient who had a metastatic tumor that was in the anterior abdominal wall so kind of on the front part of the abdomen and if you're using something like protons that stops after a certain distance you get to treat the tumor just like you do with standard radiation regular radiation without having excess radiation kind of spill out and so that's kind of the basics of radiation technology different kinds of radiation what exactly are the reasons that you are most likely to see me if you have kidney cancer a radiation oncologist you're most likely to see me if you have metastatic disease and there's a particular site that's causing a problem or about to cause a problem meaning it's symptomatic meaning usually you're having pain because it's compressing, it's growing a bone or compressing a nerve there's airway compression or there's sites that are less likely to respond to systemic therapy like brain because there's a special lining in your brain called the blood-brain barrier so a lot of drugs that Dr. Taikoti gives don't work as well in the brain as you do in other parts of the body there's also a couple of special scenarios where we use radiation to treat what we call oligoprogressive disease as well as you've already heard it hinted at the combination of radiation and immunotherapy to enhance the efficacy of immunotherapy and so what do I mean by oligoprogressive disease and so as Dr. Taikoti's treatments improve believe it or not that actually gives me more to do as a radiation oncologist because the better your systemic therapy treatments are then the more likely it is that it will matter that we need to treat one or two or three specific sites that are problematic and so this is illustrating the concept of kind of disease progression for a patient with metastatic cancer so for example these blue dots in this patient are supposed to be representing different sites and metastases so you have a couple long nodules you have a spot in the liver and you have a spot in the bone in the pelvis and these patients are on a tyrosine kinase inhibitor treatment of which something like sous-tent it's a tyrosine kinase inhibitor and so at first these drugs these spots of cancer all respond to the treatment that you're on and they're all controlled but unfortunately cancer cells mutate over time and they develop resistance and so at some point what happens is you can have one spot this little red spot here that then is starting to grow through the sous-tent treatment for example and so of course if all of your spots are growing at the same time through sous-tent then it's probably too toxic to use radiation to treat all the spots at once but if you have one or two or three particular spots that are growing but other spots are responding what you can do is you can then use radiation or surgery to treat those particular spots that are progressing in the hope that then you have more time on the therapy that's working that you're tolerating so for example even more time to sous-tent to work instead of now having to stop that and moving on to something else that may or may not be as effective and may or may not be more toxic and so I think the key here is oligo meaning a few which is radiation has side effects as well so it's only worth doing if there's a few spots and the definition of a few changes in the study as well and so, you know, I think some of this data comes from patients with lung cancer because as we saw from Dr. Taikoti's chart there are just many more of them than patients with kidney cancer but these are patients who are on various kinds of these kind of smart drugs tyrosine kinase inhibitors, different ones than the ones that are used to treat kidney cancer but similar concept that they are on these tyrosine kinase inhibitors for basically metastatic stage 4 lung cancer therapy initially works for a while so the medium progression free survival so it works for about 9 months on this one drug called chrysotinib it works for about 13.8 months for this other drug called palatinib but then at some point these patients are developing progression through these drugs and what they do is for patients who have less than 4 sites of progression they then gave pretty high doses of radiation or surgery to the sites that are growing and on average they're able to buy patients another 6 months on the same drug instead of having to switch drugs entirely and that is of meaning as well because you get to continue on a therapy that is still effective and is having a tolerable side effect profile so that's one possibility another possible role for radiation in metastatic renal cell carcinoma is in conjunction with immunotherapy because radiation we're hoping can work like a vaccine and so I won't get too much into the basics of it but basically radiation triggers what we call an immunogenic cell death meaning it kills the cancer cell releases a bunch of proteins from the cancer that are hopefully different than the proteins that your normal body has because again a cancer cell is a mutated cell it also releases a lot of chemical signals that causes an inflammatory environment so that immune cells go in and kind of are a little bit revamped into kind of responding and developing a immune response and so this is the abscopal effect Dr. Taikoti referred to which is if you have a patient who has cancer in multiple parts of the body and you give radiation to one site like that red circle presumably a tumor in the right arm here you're hopefully releasing a bunch of tumor associated antigen so abnormal mutated proteins from the cancer cells and they're being recognized by these antigen presenting cells as this is not normal they will then float around over to the lymph nodes in your body and kind of help grow a population of immune cells T-cells that are hopefully going to be specific to the cancer float all over the body and get the cancer wherever they are not just where you treat them that's kind of the ideal it's unfortunately an extraordinarily rare phenomenon to see and so it's limited to a handful of case reports and literature so for example this report is talking about a 61-year-old gentleman who had an nephrectomy in 2008 for a clear cell type renal cell carcinoma and was noted at the time of surgery to already have the cancer spread to the left adrenal right above the kidney and unfortunately about a month after the surgery they saw that the patient actually had bilateral lung nodules and abnormal lymph nodes as well as the cancer spread to the bone in a couple of thoracic vertebral bodies T-8 and T-10 and so they gave radiation to those spots in the vertebral body 40 gray and 5 fractions that's a very reasonable SBRT dose aggressive dose to give for spinal mets the patient did not get any systemic therapy there was no evidence of pulmonary infection or any symptoms of it and what they saw surprisingly was of course the radiated lesions in the spine and the bone responded but the untreated lesions, the multiple lung mets and lymph nodes actually also regressed and so what this is showing is this is a diagnostic CT scan showing this is a tumor in the lung that should not be there this is right after the surgery before any treatment this is about two months after radiation to the spine so in a different part of the body this was not treated with radiation in August it continued to get smaller and again this is a patient who's not on any kind of systemic therapy and for the published report they said that three years later in 2011 the patient was still alive and well with no new metastatic disease the patient did have brain mets that were treated with radio surgery which I don't know if you recall a few minutes ago I said the brain is a very different part of the body because it's protected by the blood bearing barrier and the environment is felt a little different and so this is kind of the dream for the abscopal effect for radiation but like I said it's extraordinarily rare and so a more likely use of radiation is in conjunction with immunotherapy that's already being used to try to make them more effective so as Dr. Taikoti alluded to IL2 it's a very common used immunotherapy it's quite toxic as well but the overall response rate isn't particularly high so this is one study for example that came out in 1995 that looked at over 200 patients with metastatic so stage 4 renal cell carcinoma that were treated with high dose IL2 and unfortunately everyone gets treated but the overall response rate is only about 14% and so out of 100 patients only 14% showed a response to this treatment with the complete response meaning all of your sites of disease have disappeared only 5% out of 100 and partial response meaning there's shrinkage of tumors but they're not gone about 9% and the figure on the right is showing for the 14% lucky patients that actually showed a response how long do they respond well the ones who had a complete response median duration of response was more than 3 years median duration of response was about 19 months so a year and a half for those who showed a partial response and so can radiation help make these odds better there was a very small study that was published back in 2012 that looked at SBRT so high dose radiation to a small area plus IL2 and they only had 12 patients 5 with renal cell, 5 with melanoma because both groups of patients are treated with this IL2 treatment and they gave high doses of radiation 20 gray 1-3 treatments and the goal was it must end 3 days before starting IL2 because you're going for that inflammatory reaction and you're trying to start your immunotherapy before the inflammatory reaction fades from the radiation and they actually unfortunately there was only 5 patients with renal cell but they saw a 60% complete or partial response rate with this group of patients who were treated with SBRT plus IL2 which is much higher than the 14% we saw in the last study so that's very encouraging so there's a larger study that's being done now we don't have the final results yet so this is called an interim analysis where similarly they're giving high doses of radiation to a small area 1-3 fractions they're allowed to treat up to 6 sites but the median is usually 2 so it's hard to treat a lot of sites of the body without causing excess toxicity and again the goal is that the radiation and the IL2 must start within about 3 days of each other and they had about 15 patients that have a long enough follow up that they thought actually like they could conclude something and right now their response rate is about 53% so again higher than what you usually expect to see with the IL2 by itself and so Dr. Tykote and I have started treating a few patients kind of off protocol on this regimen and they did not see any significant increase in toxicity when you combine the radiation plus the IL2 versus just the IL2 by itself and so we've heard a lot about PD1 checkpoint inhibitors, I promised Dr. Tykote I would not have that figure with the checkpoint inhibitors inhibiting each other but basically checkpoint inhibitors are trying to release one of the breaks on the immune system to help your body mount a more robust immune response against the cancer and this is the checkmate 025 study that Dr. Tykote actually mentioned in his question and answer session which is for patients who have metastatic stage 4 renal cell carcinoma who already received some kind of therapy and their cancer progressed through it they tested nevolumab versus what was what was more standard of care second line therapy at the time of reliance and with over 800 patients that were enrolled they found that nevolumab, this PD1 checkpoint inhibitor this immunotherapy is more effective the median survival was 25 month versus 19 month and it was also less toxic so grade 3, 4 adverse events usually grade 5 adverse events are death, 3 to 4 is serious 4 is usually meaning like hospitalizations grade 3 adverse events are usually need hydration, lots of meds maybe hospitalization so it's both more effective and better tolerated and so that's what now made it a more attractive therapy for a lot of patients but again the problem is the response rate now the nevolumab the response rate is 25% which is a lot higher than the 5% you were getting with the standard therapy but complete responses were only about 1% with nevolumab and the median duration of response is only about a year so what has a lot of people excited about immunotherapy is when you're looking at a survival curve like this and so this X axis being time so month and then this being probability of progression free survival a lot of the time with these immunotherapy agents you see what they call a tail meaning it doesn't work for a lot of patients but there's a small group of patients in this one about 15 to 20% where it works and it works for a really long time and so the question is the reason that there's so many combination immunotherapy trials out is we like this tail but how do you make this tail higher that you're benefiting a much larger proportion of patients and so there's been a lot of studies looking at radiation and PD1 checkpoint inhibition because radiation actually affects T cells your immune cells through the PD1 pathway and radiation like SBRT can actually induce PDL1 expression in tumor associated lymphocytes as well as increased PD1 expression and so it works well that when you then block it that they might work synergistically together there's a lot of studies and mice that will have survival curves that look like this where you have time on one side you have percent survival on another y-axis and what they're showing is usually that they took a bunch of mice gave them some kind of tumor and there's usually always a control group that gets no treatment at all they usually die the fastest and then there will be another group that gets just radiation there will be another group that just gets the immunotherapy and those two therapies may help the mice live a little longer but not too much longer and then radiation plus immunotherapy together will be the group that does the best and even have some mice that are cured of their cancer with a combination of two so they've done this for a lot of different cancer types and a lot of different kinds of specific drugs but we have yet to prove this in people so and so there's also been trials looking at this in people and you know beyond just radiation and immunotherapy what else can you add to the cocktail to augment the response and another promising candidate are drugs that inhibit a pathway called PI3 kinase you don't have to know what that is other than it's a molecular signaling pathway that your cancer cells use to manage to grow and escape being killed by your immune system the drugs etc and so there's it actually helps to augment response radiation this is a phase 2 trial that took a bunch of patients that have lung cancer again many more patients with lung cancer than kidney cancer they added this drug called Nalfinivir which inhibits PI3 kinase pathway to the regular chemo radiation that people get and found a much higher than expected response rate in these patients and luckily this same drug the PI3 kinase it actually also augments response to checkpoint inhibitors and so this for example is a study that looked at mice that were given a particular kind of cancer which they found that if you give this particular kind of PI3 kinase pathway inhibitor it helps to reverse another group of cells that are suppressing the immune system myeloid by suppressor cells and so what that ultimately adds up to is that you're hoping that if you combine all three then you have a tumor you're radiating the tumor it's releasing a bunch of tumor specific proteins that are being captured by your immune system taken to your lymph nodes your immune system is trying to mount an immune response these checkpoint inhibitor drugs like the one that's helping to augment that immune response and then an additional drug this now Finvier the PI3 kinase inhibitor is helping to decrease the suppression of that immune response and so we've recently actually opened up a clinical trial here trying to incorporate all these concepts for patients with various kinds of metastatic cancer including renal cell carcinoma also melanoma lung cancer where they're getting nevolumab so the checkpoint inhibitor therapy that's FDA approved for metastatic renal cell carcinoma they get radiation to a single side of the disease and on very high doses of radiation just three treatments and they get this drug this PI3 kinase inhibitor and the goal of all of this is to basically increase the number of patients that one have a response to immunotherapy and two has a durable response to immunotherapy and so I think I'll stop standing between us and lunch and there so happy to take questions yeah yeah so I think that's always been an active area of debate so like you said the study in Texas technically they allow up to six but the median was two meaning the more of your body that we treat the more we're concerned about causing side effects and so with the radiation it's really meant to be a vaccine meaning to give a booster shot and so it's felt that if you're giving a high enough dose a booster shot to one site should be as effective as wrapping six sites at once and a lot less toxic if you needed more sites to be treated because you know medical you need more treatment that's okay but the protocol specifically says you have to treat at least one so yeah so usually size is a part of it meaning you know with radiation we can't kill you with the radiation treatment and so if you're treating a large area you can't give a mass dose of radiation to a large area it's not safe right now historically the way that radiation and surgery have always worked is you have a tumor that we can see and if you're having surgery to that tumor your surgeon will not only take out that tumor but they'll frequently take out some lymph nodes around it to make sure it hasn't spread so radiation similarly often when we treat a cancer there's the cancer that we see but then we'll prophylactically treat a bunch of lymph nodes around the area to make sure that we get any cancer cells that might be trying to escape it's actually a reverse in our thinking now as we're trying to partner with immunotherapy because as I showed the immune response is bounded in the lymph nodes next to the tumor and so we're now actually intentionally trying to keep our radiation fields as small as possible so that we're not interfering with the immune response that your lymph nodes are trying to generate there's even some people that are advocating that we shouldn't even bother treating the whole tumor we should just treat the little middle part of it because again you're just giving it as a booster shot like a vaccine so why bother trying to treat the whole tumor when you're just trying to kill off of it to augment the immune response but it is not safe to give a high dose of radiation to a large area so it's only safe to do that to a small area that's probably something for your radiation oncologist to answer but usually we don't like doing it if we're treating more than 5 cm if you're trying to give the kind of SBRT kinds of doses and something's much tumors greater than 5 cm becomes less safe to do so as good as a couple large doses for generating an immune response no because we know that when you're so radiation actually kills immune cells believe it or not and so that's why when you see these studies they're all meant to be very few doses of radiation so that we generate an immune response without killing it later if I keep radiating you know the same area for 6 weeks for example I will generate an immune response initially but then I'm going to kill that immune response later down the road and so that's why when you look at the clinical trials for this it's usually like 1 to 3 doses of radiation so that you generate an immune response and then you stop affecting that immune response with the radiation if you're just trying to kill off the tumor then we also like giving high doses as high as possible as quickly as possible but again you have to factor that with safety because if you're trying to kill off the tumor then sometimes it's not safe to give a very high dose over a very short period of time