Dr. Hwu, welcome to Patient Power. First of all, do we have any clue why this cancer is rising faster than any other?

Advances in the Treatment of Melanoma Webcast May 20, 2008 Patrick Hwu, M.D. Please remember the opinions expressed on Patient Power are not necessarily the views of M. D. Anderson Cancer Center, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Introduction Hello and thank you for joining us once again. I'm Andrew Schorr broadcasting live in this webcast. Every two weeks we connect you with a leading M. D. Anderson expert, sometimes more than one, often inspiring patients and help you learn in depth about the latest in the treatment of a given cancer or situations that affect all of us as cancer patients, cancer survivors or family members. You know, one of the cancers where the incidence is rising faster than any other is melanoma. 51,000 new cases of melanoma will occur, be diagnosed this year. M. D. Anderson, of course, has a whole multidisciplinary team that deals with it. We're going to learn a lot more about it because it's obviously concerning. Melanoma you know starts as a skin cancer typically. It's a malignant form of skin cancer, and these melanocytes, as we'll learn more about, these cells, they produce pigments that give skin its color, but melanoma usually appears as an irregular, brown, black or red spot, maybe a mole begins to change in color, size or shape. And while it's only three percent of all the skin cancers it has the highest death rate of all types and is more likely to metastasize and spread in the body. And then it varies where it shows up for men or for women or whether you're fair skinned or not. We're going to learn all about that. I'd now like you to meet our guest tonight. He's a true expert in the treatment of melanoma, and that's Dr. Patrick Hwu. Dr. Hwu is chairman of the department of melanoma medical oncology at M. D. Anderson, and as I mentioned there's a whole multidisciplinary team that comes into play when we talk about melanoma. There are surgeons, there are radiologists of course, there are radiation oncologists, and there are medical oncologists. Dr. Hwu, welcome to Patient Power. First of all, do we have any clue why this cancer is rising faster than any other? Melanoma Cases Increasing Thank you, Andrew, for having me on the program. We don't totally understand that, but it is increasing in incidence as well as death rate. Part of that increase in

incidence is that people are checking their moles, and we're having more diagnoses of early stage disease, so I think that's part of the increase in incidence. But it doesn't explain the whole thing because the death rate is also increasing, so that means that people are getting higher level of serious melanomas as well, and it's not clear if that's due to the diminishing ozone or the fact that people just are not practicing sun safety measures. But the lifetime risk now in the country is about one in 70. Whoa. Now, we think we're in sort of a political year now, and one of the people who is front and center is Senator John McCain from Arizona, of course is the likely, it appears, Republican candidate, and we know in his history he was diagnosed and treated with melanoma. I haven't heard much more about it, so I imagine it was caught early. Tell us about melanoma as far as how serious it is if it is caught early and cut out or if it has gotten in the deeper layers or even spread. You're absolutely right. Melanoma if caught very early can be cured surgically. That's if it's a thin melanoma, normally less than a millimeter in thickness, it can be cut out and cured that way. However if it's thick or starting to grow thicker then it can spread, first to the lymph nodes and then to other parts of the body, and so it becomes much more serious at that point. When it's spread to the lymph nodes those are removed, but if it spreads to other parts of the body--and I've seen it go to almost any organ in the body including the brain, the lungs, the liver, then systemic therapies such as chemotherapies or immunotherapies are required at that point. Well, I know we'll have a lot to talk about related to where you are headed with the latest research related to melanoma, and you're very involved in that, Dr. Hwu. Help us understand this, though, so we talk about skin cancer, there are lots of different types and those other cancers kind of just stay there on the skin, but if I understand it from what you're saying about melanoma these cells travel. Absolutely right. They do what we call metastasize, and that's what makes them so deadly. The other types are basal cell cancer, that's also caused by the sun. That's caused by total accumulation of sunlight, but it almost never spreads. It just grows locally and needs to be removed with surgery. The other kind is squamous cell cancer of the skin. That can spread at later stages, and there are some aggressive ones, but for the most part those can also be treated surgically. 2

Melanomas can be treated surgically for those that are very thin, but even if they grow to over a millimeter in thickness then there can be a significant risk of spread at some point. Risks and Detection of Melanoma Now, I know it varies by person and skin type. Help us understand, though, what melanoma looks like. I'm sure we're all like checking our skin and our moles. And at what age also does this show up? So melanoma can show up at just about any age. In fact it's one of the most common cancers in young adults age 20 to 30. It's the primary cause of cancer death in women 25 to 30 years old. So people of all ages can get melanomas. There are a number of things to look for in trying to determine if a pigmented lesion is just a regular mole, which is nothing to worry about, or a melanoma. We call those the ABCDs. A is asymmetry, which means the right side doesn't look like the left side, it's asymmetric. B stands for border, meaning the border is irregular. C stands for color, meaning there's a variation in color such as another pigment, some red or another color in a normally black or brown nevus. D is diameter. If the lesion is larger than the size of a pencil head eraser, about six millimeters, then it's something that you need to be a little more careful of and evaluate more closely. E stands for evolution. So if the lesion changes then that should definitely be checked out by a dermatologist. People should do self examinations, and if any of these signs are there then they should see a dermatologist for a biopsy, which is the only real way to determine what the lesion is. So people especially of fair skin we recommend that they see a dermatologist for screening at least once a year. Wow. Okay. Now, I've heard that redheads are more at risk. Is that true? People with really fair skin, maybe freckles, red hair, are they at a higher risk? Yes, so anybody can get melanoma but you're right, it's much more common in people who have lighter skin, and people who have red hair often have lighter skin so they have less pigment that protects their skin from the sun's UV rays. So that's likely the reason why they get more melanomas. There also may be some issue with the kind of pigment they have that might induce melanomas, but that's research that we don't totally understand yet. For the most part, though, those people who have light colored, very light skin are less protected against UV rays. 3

And I've heard also that people with darker skin, though, could still get melanoma under your fingernails, your palms, the soles of your feet. Absolutely. Even black people can get melanoma, and that's called acrolentiginous melanoma, which is on the palms and on the bottoms of the feet. There is also melanoma that you can get in the rectum or the vagina, and that's called mucosal melanoma. And so those are very different diseases. They're obviously not caused by the sun, but they have a different cause that we don't totally understand, and they probably should be treated differently. They're quite rare, but we see a good amount of it at M. D. Anderson. Well, of course you're such a center where people come from all over the world there, and as we talked about you have a big team. So when somebody gets a diagnosis of melanoma, typically from a biopsy, is it a one-size-fits-all, or could it vary? In other words if someone else is sitting in the waiting room might they have the identical biological signature to their melanoma, or might it be different, and ultimately there might be different treatments that come into play? I think that right now it all depends on how thick the melanoma is and depending on how we initially treat the melanoma and where the melanoma has spread to. If it has spread to the lymph nodes or spread to other parts of the body as well as what it looks like under the microscope and where it started; that's how we currently gear our therapies. But in the future we're starting to personalize therapies and looking at the light switches that turn on or off the melanomas so that we can give the right medications because every melanoma is probably molecularly different. For example the kind of melanoma that you talked about that starts on the palms or the bottoms of the feet or that starts in the mucosal surfaces such as the rectum, that's a very different kind of melanoma, and we're learning that there's a kind of receptor, a signal called c-kit that might be changed in a way that we would give a specific medication for that called a c-kit inhibitor. It's a pill such as Gleevec or other pills that are coming out that inhibit c-kit. So if we have a patient and we find that they have a mutation or that means a change in the DNA of that light switch, which is the receptor, we will then give them a specific medication that will inhibit or turn off that light switch. That's exciting. So basically, as we've talked about in other cancers, we may be able to understand the biology of someone's specific cancer in them. Now, what about genetics? People have been writing in already with e-mails, and they say, well, you know Dad had melanoma and was treated for that. Am I at risk? And 4

one lady wrote in and said, well, then also it's so curious, we all have darker skin as well. But is there a genetic factor going on? So there are families that have a syndrome called dysplastic nevus syndrome, just a lot of funny looking moles is what that means, and they tend to have more melanoma. But yet most of the melanoma that we have aren't in any families that we can identify. There probably are some factors that we don't totally understand, but there are also some environmental factors. For example the number of sunburns that you have as a child does correlate with your risk of melanoma. It's really the intense exposure to UV rays, the number of sunburns, that correlates with that. So if a family has lived at the beach or in the state of Texas for that matter because the sun is so hot here, they may have had more UV exposure. And it's interesting that although light-skinned people get more melanomas people of all kinds of skin get melanomas as well. Well, you know, here we are, it's summertime, depending on where you are, or about to be, and so we wonder about going to the beach. And I have children, and should we slather them with sunscreen? I've got my 11-year-old trained now. You know if there's anything, even clouds, he says, Should I wear sunscreen? Should I wear sunscreen? So when we come back after the break we want to understand more about those early maybe heavy-duty exposures to the sun when we weren't cautious that we may have had as a child or a teenager and whether some people are paying the price with melanoma that's developing years later. Prevention Welcome back to our live M. D. Anderson Patient Power webcast. Andrew Schorr here with Dr. Patrick Hwu, who is chairman of the department of melanoma medical oncology. We're talking about melanoma today. Just before the break, Dr. Hwu, I was wondering are we paying the price for not taking care of ourselves when we were younger. You know teenagers I think are notorious for not using sunscreen. Years ago we used to use all that Coppertone stuff. It was about getting tan, tan, tan, but maybe not protecting our skin. Is that what we're paying the price for, just being sun worshippers when we can and not taking care? Certainly sun exposure as a child can predispose to melanoma years later. Unfortunately there's nothing we can do until we invent a time machine to go back and change that, but at any point in your life if you decrease your sun exposure you will decrease your melanoma risk. 5

All right. Let's take that further now. What should we be doing? I want to talk just for prevention for a minute, and there are many people listening of course who have been already diagnosed with melanoma, but they say, Okay, I can't rewind the clock for me but for my family members as we go into the hot weather now, what should we be doing? Like what about with your family? Do you go out in the strong part of the day or wear sunscreen? What do you do? Yeah, it's a tough thing, especially living in Texas, and I have one child that's got very fair skin. What we do is practice basic sun safety measures, and we try to avoid being outside in the direct heat of the sun; that's when your shadow is shorter than your body, then you have to be careful. That means the sun is directly overhead. Usually around the time between ten and three, that's when you have to be most careful outside. And when we are outside we try to seek the shade. There's nothing better than staying out of the sun. The shade definitely does shield you from some of the UVA and UVB rays. I try to encourage people to wear a hat as well as protective clothing and sunscreen, sunscreen that blocks both UVA and UVB rays with at least a sun protection factor of greater than 15. In addition if you're out swimming and other things you have to reapply that sunscreen often, every couple hours or so. Good point. I also tell people to try to avoid sun lamps and tanning beds. All right. Couple questions. While you're saying that, I just want to underscore that. So tanning beds are not a free ride as far as the rays that can lead later on to melanoma? No, because both kinds of UV rays, UVB and UVA, can damage DNA. UVB damages DNA directly - the DNA is our blueprint that tells our cells how to divide and make ourselves who we are. If we have a mutation in the DNA, that can cause cancer. UVB rays can directly cause changes or what we call mutations in the DNA. UVA rays can indirectly cause those mutations by inducing a kind of molecule called a free radical, which actually comes from oxygen. So both kinds of rays can cause damage to DNA, so that's why we have to be careful. 6

And I think that the suntan industry has launched a program to try to say, You know, there's really no evidence that sun tanning on a suntan bed causes melanoma, and those studies, though, are very hard to do because people are exposed to so many things. You almost have to randomize people to go get sun tanning in a suntan salon versus not, and you can imagine those studies would take years to do and no one would participate in them. So it's often very hard to show that. But what we do know for a fact is that UVA rays and UVB rays damage DNA in melanocytes, which can then lead to melanoma. Okay. You wouldn't be happy if your young child was going to a tanning booth? No. She would not. Okay. I got to talk to my daughter about that. Just a couple of quick questions then I want to get into the world of treatment. So people do wonder about sunscreens though and you used some numbers. Do the numbers make a difference? Alex wrote in from Vero Beach, Florida and said, "Well is there a big difference between SPF 60 and 45? And is sunscreen helpful in preventing melanoma?" It's interesting because those studies are again hard to do, and when they've done those there have been some studies that have shown there's less melanoma and some studies that have shown there's no difference and some studies that have shown there are more. And so I think that one problem is a lot of the studies, because they take many years to do, were started in the days when there was just suntan lotion that blocked UVB, but it turns out that UVA is just as important to block. I think the studies done with suntan lotions that block UVA and UVB have not really been done yet. In addition, sometimes people feel bullet-proof with suntan lotion because they're not getting burned, their UVB is being blocked, and they're still getting a lot of UVA exposure and getting a lot of sun exposure that might damage the DNA of their melanocytes and yet because they're not getting burned they stay out in the sun longer. So I think that's also something. Just because you're not burning because you have suntan lotion on doesn't mean that you should stay out in the hot part of the sun for a long period of time. You still are increasing your risk. But my feeling is if you block UVA and UVB that will decrease your melanoma risk. The better thing would be to stay out of the sun altogether, but if you're in the sun it would be better to block that UVA and UVB with sunscreen. 7

Is there a difference between 15 and 45 or 60? I don't know that studies have shown there's a great deal of difference once you get past 15. Boy, I plead guilty to all those activities, falling asleep on the beach and all these kinds of things and feeling confident because I didn't burn. One last question because it's been in the news. There was a study, and I think there's more coming out at the big cancer meeting, that vitamin D I think helps lower your risk of breast cancer, if I remember what I saw in the news release, and we'll find out more about that. So what about the benefits of vitamin D? We want to get our vitamin D from the sun, but then we don't want to damage the DNA of our skin cells to develop melanoma or any of the skin cancers. Very good point. Those studies started because it turns out breast cancer--the closer you get to the equator the less breast cancer you see, so they were trying to research that. And it does look like vitamin D levels and breast cancer have an inverse correlation. And vitamin D, the most active form of vitamin D is produced by the sun's rays. I think it's called vitamin D3, but you can get that by just a few minutes a day of sun. We get that in Texas just by going from our offices to the parking garage and back every day. That's plenty of sun to get your vitamin D. So I think that that does not give people free license to go out and suntan for hours and hours or go to tanning salons. The tanning salon industry is trying to say that that is a health benefit, going to a tanning salon, but I think you can get that, especially in a place like Texas, with just a few minutes a day, and you don't have to go to the beach for that. Plus there are ways to get vitamin D with oral supplements. Testing for Melanoma Okay. Well, I can't quite get it between the parking lot and my office in Seattle on some days, but I get the idea. You don't need a lot, and maybe you can take a pill as well. I want to start our discussion about treatments. So somebody is diagnosed with melanoma. It's a scary diagnosis, although happily like with John McCain he's going on, and he's planning a big future for himself and maybe in politics. So there are people where it's caught early and this works out pretty well. But unfortunately I know it often can be more advanced or the fear is that there may be microscopic cancer cells that have travelled. Besides the biopsy, then, what sort of tests do you do to try to get a handle on has the cancer spread? 8

Okay. So if the lesion is very thin - we just do what is called a wide local excision. The surgeons will just take surrounding tissue and cut that out. And that will be it. But if it's over a millimeter or has any signs of danger based on the pathology analysis, then we will do what's called a sentinel lymph node biopsy. That's a procedure that certain melanoma surgeons do in which case they try to track what lymph node that lesion drains to. A lymph node is an organ in the body that has immune cells in them. Tumors spread that way. They go through the lymphatic channels into the lymph nodes and eventually then go into the blood stream and spread. So that's kind of the road by which they travel to spread through the body. So by isolating with dyes and radioactive material the surgeon can isolate the lymph node that services that area of the lesion. They can then track down and figure out by biopsying that lymph node if there is tumor in there. The pathologist will then look very carefully at that lymph node, and if there's no tumor there then nothing else is done. Treatment is done. If there is tumor there, though, then the surgeon needs to go in and cut out other lymph nodes in the area to try to determine whether there are other lymph nodes that are positive or not. So is that what lymph node mapping is? Yeah, that's called lymph node mapping or sentinel lymph node biopsy. Okay. So let's say the map shows some travelling cells there. What happens next? Then the lymph node dissection is done in which case multiple lymph nodes in that area are taken out. After tht, therapies are offered to try to prevent that tumor from coming back after we do scanning on the patient to see if there is disease in other places of the body. So if the lymph nodes are positive we would then do a scan of the brain with an MRI scanner and a CAT scan of the body. And if there's other tumors there then what we'll do is systemic therapy that we will talk about in a second. But if there are no tumors anywhere else and we can't find any evidence of disease on the scans, then we'll do one of three things. Either we'll just frequently watch the patient with scans every few months. Or, number two, we'll offer a kind of therapy called interferon alpha, which is a natural protein which stimulates the body's immune system. Or, three, we'll try one of our clinical trials, our cutting-edge studies such as a vaccine. Both of those last two options stimulate the body's immune system. 9

We have a lot to talk about. What I'd like to do, Dr. Hwu, is take a break and invite people to send in questions. They can send them into patientpower@mdanderson.org. Patientpower@mdanderson.org. You can give us a call, 877-711-5611. And Jamie, our producer, is happy to take your questions. And thank you, folks, who have been sending them now. We're visiting with Dr. Patrick Hwu. He is chairman of the department of melanoma medical oncology at M. D. Anderson, and we're going to learn more about the treatments. Now, of course at M. D. Anderson they have standard therapies if that's appropriate. They also have a lot of experimental therapies and clinical trials, and that may apply. And there are things like vaccines and T cell therapy. We're going to learn all about that as we continue our discussion on our live webcast. Stay with us. You're listening to Patient Power sponsored by M. D. Anderson Cancer Center. Treatment Welcome back to our live webcast. We're going to spend the second half hour talking all about treatment. What's standard therapy? Where do we go from there? Now, you we understood from Dr. Hwu, who is our guest with us, who is chairman of the department of melanoma medical oncology at M. D. Anderson about surgery and hopefully that's it for a lot of people, but unfortunately there are people where that isn't it. And then we need to go on, as you started to say, Dr. Hwu, to systemic therapy. So help us understand what that's all about and what some of the options are. And we've been getting in questions from people who have more advanced cancer, like stage IV, and want to understand what's available for them as standard therapy and also where your research is headed that you might offer people in clinical trials. So, first, help us understand the standard approaches that you have available. Okay. So as we were talking about if the disease has spread to the lymph nodes but nowhere else we can remove the lymph nodes, and then the standard treatment in that setting--it's called adjuvant therapy--is interferon alpha. And that works by stimulating the body's immune system to try to stimulate those immune cells throughout the body to try to rid the body of tumors that might be hiding out in different areas of the body. So that's the standard treatment. The cutting edge clinical trial that we have is using vaccine therapy, and that's a way to more specifically stimulate the body's soldiers called T cells. And with those vaccines we hope to increase the number of those circulating T cells in the body to 10

then go out and seek potential tumor hiding out. Those vaccines are best used, I think, at early stages where we're trying to prevent a recurrence. Now, you mentioned that some patients come with more advanced disease such as already spread to the lungs, to the liver or other parts of the body, and in that case we would go with other systemic therapies. The standard therapies in this case are chemotherapies. The one that's FDA approved is called dacarbazine. That's an intravenously administered drug. There is also an oral form called temozolomide. And those are the standard agents that we use for disease that has spread to other parts of the body. However, many times it doesn't work well, and if we see a regression of disease it's not long-lasting. So we have a couple of broad therapeutic approaches that we're working on at this point. One is to stimulate the body's immune system, and the other is to try to understand these signals that are turning that tumor on and then turning them off with appropriate medications. First I guess we can talk about the immune therapies. Sure. Now, I just want to go over something so everybody understands. So when you develop cancer, inappropriate cells, your immune system has let you down, because I always have this image of like a bug zapper like you might have in the summertime out on your back porch that's trying to kill those bugs that would be undesirable. Well, in a sense isn't our immune system, maybe our T cells too, like a bug zapper, in a way, looking for errant defective cells and getting rid of them, clearing them out, and when we develop cancer our immune system let us down, was blinded somehow? Yeah. We basically have an immune system to fight against viruses and bacteria. That's why we evolved an immune system. And the trick about our tumor that makes it so hard for the immune system is the tumor comes from our own cells. So usually the immune system is trained not to attack our self, so when the self goes back and becomes a cancer that sometimes confuses the immune system. It's possible that many times the immune system is successful at killing that cancer. Of course we would never see those patients in the clinic because they wouldn't have cancer. So it's possible that all the patients we see to some extent the immune system has failed to recognize that cancer and that's why the cancer is growing. So there you are. You have immunotherapy you're working on to get the immune system going again or to recognize the cancer it missed the first time. So take us through where you are now in helping either retrain the immune system or giving it a helping hand. 11

So our standard therapy to stimulate the immune system is with Interleukin 2. That is a natural protein made by our body's immune cells that stimulates and activates any immune cells that are there. So that therapy can actually cause regression of diffuse metastases sometimes lasting a long time, even years. And that's probably because when we can get this therapy to work it probably stimulates what's called memory cells, and those memory cells stay around for years and years can continually battle that tumor from coming back. The issue with that therapy, though, is that it works about 15 percent of the time, meaning 85 percent of the time we don't see a response, and we're trying to figure out who it works with and who it doesn't, but we don't know that at this point. And it can be quite toxic. We have to give that in the intensive care unit. Although patients that have a good performance status, meaning they don't have other diseases, can often tolerate the Interleukin 2 therapy. But the reason we give it is because if we can get it to work it can work for a very long time. But our goal is to get immune therapies that work in more patients of course. So we're trying a number of clinical trials at this point. Take us through some of that. Well, one kind of therapy that we have is a combination of chemotherapy with Interleukin 2 and interferon all together. That's called biochemotherapy. We think that stimulates the body's immune system because the chemotherapy destroys the tumor and probably releases antigens, and then we drive that immune response with the natural proteins Interleukin 2 and interferon. That treatment is also associated in some settings with disease free intervals that can last years, meaning that patients can have no disease ten years out if it works in this setting. The response rate is about 30 percent, with about half of those lasting at least for a number of years. Our most recent therapies involve T cells. In every melanoma tumor lesion there are some immune cells trying to do the job. They are in the tumor but obviously they're not doing a good enough job because the tumor is growing. So what we've learned to do is take those tumors, grow out the immune cells in the laboratory to billions, and then give them back, along with Interleukin 2. We call that T cell therapy. And the response rates to that have been in the order of 50 percent. So that's really the most effective therapy that we have to date for disease that has spread, (metastatic melanoma). We hope to try to improve the duration of the responses that we're seeing and make it more effective and less toxic. It's another therapy--because it's given with 12

Interleukin 2, it that has to be given in the intensive care unit as well. So we're working on ways to improve this therapy and we're also trying to generalize these scientific principles to other kinds of cancer such as breast cancer and colon cancer. Vaccine Therapy Some people have heard about vaccines that have been in development for melanoma, and some of the early ones just haven't panned out. You still have faith in vaccines. Where are you at M. D. Anderson with that, maybe later generations of vaccines that could help lower the risk of recurrence of melanoma? That's a good point. I think there are many different flavors of vaccines, and many of the vaccines that have already undergone big trials were developed 20 or 30 years ago, so they're not our latest. We've learned a lot about the immune system since then, and so that allows us to really be much more molecular and targeted in our ability to stimulate the immune system. We've learned exactly what the immune cells can recognize on a melanoma, and we've made those molecules in large numbers, and we give those to patients as vaccines, and I think it's potentially much more effective in stimulating the body's immune cells. We do know that if we compare the patient's circulating immune cells before or after the vaccine we see in the vast majority of patients a lot more immune cells that can recognize and kill the tumor after the vaccine compared to before the vaccine. So we have a lot of hope now for our current generation of vaccines that stimulate the body's immune response. We're also giving vaccine helpers, called vaccine adjuvants, that simulate viral or bacterial infection. Because that's why we have an immune response. Our immune system gets very activated when it thinks there's a virus or bacteria. When you get the flu the reason you have a fever is not because of the flu it's because of your immune response against the flu. So we're taking little bits and pieces that look like viruses and mixing them also with our vaccines to try to trick the body into thinking that there's an infection going on, and hopefully we can then harness the power that the immune system has normally against viruses and bacteria and trigger that against the tumor. Dr. Hwu, I'm going to fire some questions at you that we've been getting in, but just one last thing to put it into perspective to folks. Some of the approaches you're talking about are going on only at M. D. Anderson as you help lead the way in research, right? So if somebody chooses to come to M. D. Anderson and hear about clinical trials, sometimes these are trials that are just starting at M. D. Anderson, have not gone around the world yet. Is that right? 13

Absolutely. Many of the studies that we're doing are just offered at M. D. Anderson Cancer Center. We have a vast variety of studies. Some of them are standard therapies that can be obtained at other places, but we have a large menu of choices that we can tailor to a patient's own individual needs and many of those are only available here, such as our T cell therapy trial. Right. Well, for me and leukemia, it was CLL, I was in an M. D. Anderson only trial, and as I tell people time and time again that trial worked out well, and that's what most people get today around the world, but it started right there in Houston, and that's what brought me from Seattle to Houston, and as a 12-year survivor now I'm really glad I did. We're going to take a quick break and when we do we have some questions for you. Sean sent in a bunch of questions about a type of melanoma, I hope I can pronounce it right, acrolentiginous melanoma and questions about stage IV, understanding what's standard therapy, what's in clinical trials, what are the efficacies. And also how does a patient decide in consultation with the experts there at M. D. Anderson. So fasten your seat belt, Dr. Hwu, as we pose some questions for you. Acrolentiginous Melanoma Andrew Schorr back with you live. We do this every two weeks. In two weeks, June 3rd, we're going to have with us Dr. Carmelita Escalante, and one of her favorite patients, the patient calls the doctor her angel because she helped her with fatigue. We're going to have Eva with us. But we're going to talk about fatigue and the cancer patient. Eva was treated for breast cancer, could barely move from fatigue, even a couple of years after treatment. Well, now she runs races all around Houston. So it's a great story. That's in two weeks on Patient Power. Let's get back to our discussion on melanoma with Patrick Hwu, who is chairman of the melanoma medical oncology department. Dr. Hwu, so I mentioned before the break Sean wrote in about stage IV melanoma and wanted to know more about the treatments for that. I think this was one called--did I get it right? Acrolentiginous. 14

Right. So where are we with treatments for that? That's a kind of cancer that we talked about earlier that starts on the palms or the sole of the foot, and it's probably less related to sun exposure. We're learning more things about that kind of cancer these days. Some of those cancers have that change in the c-kit receptor that we talked about, about 15 percent, I would think. So I think with acrolentiginous cancer we're just now beginning to understand this, but I think what we need to do is sequence the DNA from those tumors, and we can do that at M. D. Anderson, sequence those tumors to see if there's a mutation or change in that c-kit receptor, and if there is then we would recommend probably an inhibitor of c-kit, which can be given in pill form. Now, if the c-kit gene is not mutated then we would with go with one of our standard therapies depending on whether he's had previous therapy or not and what other potential health problems he has, we would tailor a treatment for him based on chemotherapy or in combination with chemotherapy or immunotherapy or possibly if something is resectable removing it to try to grow some of those immune cells called T cells. It would all depend on his individual situation. So as I understand it with that c-kit receptor you're talking about, that's a case where--and I know it's the minority of melanomas, but that's a case where there may be drugs that have been developed and approved in other cancers that because of their makeup and in this case the biology of the melanoma they might be a match. That's exactly right. In fact that c-kit mutation, the reason we know so much about it is it's also in another kind of cancer, a sarcoma called gastrointestinal stromal tumor or GIST. And in those tumors there are c-kit inhibitors that patients have miraculous responses to, such as Gleevec and other oral inhibitors of c-kit. So that's why when we saw this mutation in c-kit we were very excited and we thought, Well, since the patient has this mutation, we're going to try the same kind of treatments that is used in GIST. And that story is still evolving in melanoma, but it's something because we have such strong data in GIST, I think it's something we can recommend today, at least to try. Deciding on Therapy All right. Now, at this recommendation part I want to talk over with our audience for a minute. We have a worldwide audience and there may be people like me who before I was diagnosed with leukemia had never been to Houston and certainly 15

didn't know much about M. D. Anderson, made me find out fast. And I think this is an important point for people. First of all, you heard it's important to understand not only the stage of your cancer but also begin to understand the biology of it, and then you have you to say, Well, who is learning about this and researching this more than anyone else? So then you have subspecialists like Dr. Hwu and the whole team at M. D. Anderson, and I would urge you to have a consultation. I would say go to M. D. Anderson, a place like that where as I like to say they eat, drink and sleep this. So if your melanoma, which can be deadly, is more advanced you want to have that understanding. Imagine if you're in that percentage of patients where a drug that was developed for a different cancer is a perfect match maybe for the biology of what you have. Now, I know you were trying to work on that much more broadly in melanoma too. How do you have a discussion with a patient where you have some standard therapy, sir, and then you have these areas of research to try to help them understand the science and then make a decision with you on which plan they might want to go with? I think that, number one, we would determine which possible therapies the patient is eligible for. And that would depend on where the tumor is, also how they're feeling, how much energy level they have and other health problems they have. If they're older and they have multiple health problems such as diabetes and heart disease we would be more limited in terms of what we would offer, and we would offer a more gentle chemotherapy agent or one of the oral agents or one of the clinical trials that is associated with less toxicity, such as one of our targeted agents which we would hope would have less toxicity than one of our standard agents. Now, if the patient, though, has a disease that we could resect to grow T cells, that almost is the most effective therapy that we have if we think that the patient can tolerate that kind of intensive therapy, and it is intensive therapy with Interleukin 2 and chemotherapy and T cells all put together. If we feel the patient can tolerate that, that is something we would offer as long as there is a tumor that we could cut out to try to grow those immune cells, and we can only grow those about half of the time. But then when we give them to patients the response is in the 50 percent range, so I think it is one of the most effective therapies for advanced stage melanoma. Otherwise, of course we would offer standard agents as well such as chemotherapies or high-dose interleukin-2 or combinations. And sometimes the patients will want to try some of the standard agents such as high dose interleukin-2, and we can try to stimulate the body that way, and if it works, great, then we're done because oftentimes those responses can be durable. But if it doesn't work then we can move on to something more experimental including the T cell therapy or one of our new targeted agents in which case we're trying to target 16

specifically certain light switches which are in the tumor. Multidisciplinary Approach Now, I want to understand more about your team there. So when it comes to melanomas at M. D. Anderson you have surgeons, I think you also have dermatologists, medical oncologists, radiation oncologists. You have a whole group and you discuss these cases, so when you're making a recommendations to someone it's often been talked about by a big group, hasn't it? Yes. We have a wonderful multidisciplinary team. So our dermatologists see the earliest of stages and also do skin cancer screening tests, and then our surgeons do resections of primary lesions as well as the lymph node mapping that we discussed and do lymph node dissections and then also sometimes even surgery in a metastatic setting, and they're wonderful partners. And medical oncologists, like myself, see patients with more advanced disease and give them the chemotherapy, the immunotherapy or the T cell therapy. But we do all work together. We're in the same clinic at M. D. Anderson. One of the ways that we interact and what we're known for is to have these multidisciplinary clinics where the surgeon is just down the hall from the medical oncologist, and we're constantly discussing patients in real time right there. If there's a surgical question that I have for a patient I just walk down the hall, and there's always a surgeon and a medical oncologist and a dermatologist in the clinic at the same time. So I just go down the hall and ask them a question and it's often very helpful. We also have a more formal conference once a week where we discuss the most challenging of cases for which we need a multidisciplinary approach. And that conference includes not only the surgeons and the medical oncologists but also radiologists and radiation oncologists as well as pathologists. Well, it sounds like a lot of brain power brought to bear for the benefit of patients who may come from around the corner or around the world. Let's kind of go back up to the 10,000 foot view, sir. You've been devoting your life to this, and we have a long way to go, it sounds like, in melanoma, and we're picking off certain areas and some existing drugs are helping for a certain percentage of patients and you try and understand exactly who, but we still have a ways to go in lowering the death rate. And of course we the public have to do more in lowering the incidence of it. But looking at your crystal ball and what you see in the lab and the 17

incremental changes, are you hopeful that we can lower the mortality of this disease, lower the recurrence rate so if somebody has it cut out or you give a systemic therapy that hopefully they can go on to a long life? Yes, we are committed to that goal. Committed. We feel it's absolutely possible. It's a very exciting time in cancer research in which case we're learning the molecules that are turning the cancers on and off. We also know a lot about what's turning the immune system on and off, so we can manipulate this. So I think what we need to do is as rapidly as possible translate things that we find in the lab into the clinic and come up with the right combinations of agents. There are a number of immune agents now that are out there in the clinic, and we have to combine them in the right way. And I think if we can do that there's a lot of hope. We have to combine them with standard therapies. We also have to combine them with the new targeted therapies. In the olden days we just mixed stuff together and we hoped it worked, but now we have to go to the lab and really try to put together combinations that are really rational scientifically, and that's what we're in the process of doing. My feeling is some really golden combinations are even available today if we can just figure out the right combinations and the right sequence of therapies. And there are also new drugs being developed all the time, so we're very excited about that, and I do hope that we can drop this the death rate. We absolutely have got to do it. There is no alternative. One point I want to make is we're all in it together. So for our listeners who are diagnosed with melanoma and hopefully seek care at M. D. Anderson or at least a consultation, part of the discussion may well be a clinical trial that you will evaluate together with an expert such as Dr. Hwu and see whether it's right for you. If you choose to be in a clinical trial, as I did, that may help move the ball forward, may give you the benefit of tomorrow's medicine today. And, as we heard, we're all in it to try to help the people who follow us as well. So I hope we're all in alignment there, right, Dr. Hwu, as far as everybody working together. Absolutely. It's a partnership between clinicians, patients, laboratory investigators, everyone working together, our wonderful philanthropists, everyone helping us and working together with the thought of just trying to eliminate melanoma and hopefully other cancers as well as we learn principles that improve vaccines and other treatments. 18

Right. Well, thank you so much for all you do, Dr. Patrick Hwu, chairman of the department of melanoma oncology at the University of Texas M. D. Anderson Cancer Center. Thank you so much. We'll have you back sometime. Next time I hope we can talk about a lower rate of melanoma. This is what we do on Patient Power every two weeks with M. D. Anderson so take a look at the Patient Power section of mdanderson.org. Remember, knowledge can be the best medicine of all. Be with us, two weeks, "Fatigue and the cancer patient" with Dr. Carmelita Escalante, her patient Eva, who calls Dr. Escalante her angel. Thanks for being with us. Have a great night. From Seattle, I'm Andrew Schorr. Please remember the opinions expressed on Patient Power are not necessarily the views of M. D. Anderson Cancer Center, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. 19