Cognitive Challenges After Hormone Therapy August 26, 2009 Webcast Monique Cherrier, Ph.D. Celestia Higano, M.D. Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, 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 Although you frequently hear about the side effects of cancer treatment like nausea, you rarely hear about how these treatments, specifically hormone therapy for example for advanced prostate cancer, can affect your memory. Coming up you'll hear from two leading experts, clinical investigators about what they are learning about hormone therapy and its lasting side effects on cognitive abilities. All coming up next on Patient Power. Hello and welcome to Patient Power. I'm Andrew Schorr. Thanks to Seattle Cancer Care Alliance for helping with a whole series of programs connecting you with leading experts. Now, as a leukemia survivor I often thought, and so did all my friends who were patients, that the heavy-duty drugs that we received caused chemo brain, so we just couldn't think as clearly, couldn't remember names. Or was it just that we were in our 40s or 50s or 60s and were just getting older, or was it the drugs. And if it was the drugs was that an effect just short term or later? Well, now it's being studied more. Specifically we're studying about hormonal therapies in men who have been treated for prostate cancer, often men with more advanced prostate cancer, not always, but if they've received hormonal therapy trying to understand does that have an effect on thinking, if you will, and on memory. Well, you're going to meet two experts who have been studying this from the University of Washington associated with the Seattle Cancer Care Alliance. First let's meet Dr. Tia Higano. Dr. Higano is professor of medicine, she's a medical oncologist at the University of Washington, the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, and she is a prostate cancer specialist. Dr. Higano, thanks for being with us. So tell us about the history of this study. Hormonal Studies for Prostate Cancer Hi, Andrew. It's nice to be here. The history is very interesting, and it's something that I have lived through actually in retrospect a very important era in history where we went from treating only men with prostate cancer who had metastatic disease with hormone therapy to treating patients who had much earlier disease 1
without any evidence of metastases but who had a rising PSA. We were only able to do this once we had the PSA test, and that wasn't until the mid 80s and wasn't really in broad use until the early 90s. So we had a group of patients who didn't have anything else wrong with them except their PSA blood test was elevated, and they were started on hormonal therapy in an attempt to control the PSA and make it go down, and usually in that situation it worked very well. But what we were finding out, we were hearing from patients when we saw them in clinic, there were some complaints. And interestingly oftentimes the complaints came from the spouse, and I would hear things like, you know, does this hormone treatment do anything to like the way my husband thinks because usually he always used to do the checkbook and now I have to do it. Things like that. And when you hear these things over and over you kind of wonder, well, this is nothing we ever were taught in medical school, that hormonal therapy changes the way you think, but maybe it really does. And that is how we started looking at this very carefully in a research study, and I enlisted the help of Dr. Cherrier, who is an expert in looking at hormones and men's thinking. All right. Well, let's meet her. So your co-clinical investigator Dr. Monique Cherrier, who is a neuropsychologist, and she is the director of the University of Washington memory health research program. So how do you study this, Dr. Cherrier? And I know you've completed one study and you have another one going on. So how do you study it? Do you give someone a test, a memory test? How do you study it? That's an excellent question, Andrew. We use a combination of things. One thing that is very important is of course we want to get the patient's perspective on what they're experiencing, so some of what we give is just simple questionnaires that try and ascertain the nature and the severity of some of the cognitive symptoms. So it will be just like a checklist where you check off, yes, I am having trouble thinking of words, and maybe how often that happens and whether or not that's a change from how you were before treatment. How do you sort it out from age? Like, as I mentioned in my introduction, somebody says, well, you're 50-some-odd years old, you're not as sharp. Right. That's an excellent question. The other way we also ascertain cognitive difficulties is we actually give paper and pencil and computerized tests, and these tests are a combination of clinical measures and experimental measures, and for some of our clinical measures we have some of what we call norms. They're basically tables of information that indicate, for example, how does a 50-year-old male with a high school education, how well do they do on this similar test, you know. So we're able to compare and see what is expected for your age and education, and that way we can kind of help tease out what is the difference 2
between normal aging or maybe some other process that might be going on or the effects of the medication or even another potential medical problem. Dr. Higano, where are we now with our understanding? So you've done one study. Is there one drug that's a particular bad guy, and is there in fact a link between the hormonal therapies broadly or even specific ones and affecting your thinking? I think it's important, when we're talking about hormonal therapy I think we need to be specific because there are a broad number of agents that are termed hormonal even in prostate cancer. So we're talking about hormonal treatments that are meant to lower the testosterone or male hormone levels. There is actually, as far as we can tell, no one culprit. Any of the agents that lower testosterone level are problematic. And again I will let Dr. Cherrier discuss how problematic because we can talk about what we've seen in our research, but again there is no one agent that we're more concerned about than others. All right. Let's answer this problematic question. How problematic, Dr. Cherrier? Well, of course it does vary from one patient to the next. We've had some come through who have noticed no discernable change once they're on hormone therapy, and we've had others who've definitely reported that they've noticed a change. Some of the more common symptoms that people report include things like difficulty multitasking, or some more dramatic changes that other people have reported for example include someone who previously was a surgeon who was now having difficulty with kind of spatially configuring and transforming and thinking in their minds spatially in three dimension how to perform surgery or other things like that. And that's been a similar report for some men who for example like to make things at home in their shop, you know, carpentry type work. And that's basically what our research has also implicate is that although some people have no difficulty at all if there's one or two areas that seem to be more affected than others it would be in the area of spatial abilities and sometimes spatial memory and then multitasking. And multitasking is doing two things at once, remembering where you left off and coming back to it and being able to simultaneously perform two or more tasks. As I mentioned, so you've completed one study, but you have a new one. What's the study that's open now? What's that about? So the new study is looking at men who are about to start intermittent androgen deprivation, and whether or not you go on what they call continuous androgen deprivation or intermittent is always a discussion with your physician, and 3
Dr. Higano can even speak to a little more detail about the differences between those two. But basically we're trying to enroll men who, before they go on intermittent androgen deprivation, we try and obtain a baseline using our paper and pencil and computerized tasks before they start the treatment because that's very important to know of course before you start where you are. We also measure using the same tasks after they've been on the treatment for one month and then after they've been on it for nine months. And although it varies from provider to provider how long a person stays on androgen deprivation therapy there is some indication that a nine-month period is fairly optimal for treatment outcome. And then we'll also test the individuals then once they cycle off. So the intermittent treatment is course you're on for a while, and then you go off the treatments. And of course what happens during that time is that you're at your normal hormone levels before you start, during the treatment then you're basically at castrate level or essentially no testosterone or androgens circulating, and then once you cycle off the treatments, so you're no longer receiving the androgen deprivation regimen, then it takes a while for you to cycle back up to your normal levels. And so when we test on the off-treatment period it's, you know, when you've been off the treatment for about six months. And then this study that we're doing now is a little bit novel in that we're also having the men once they cycle off they'll be randomized for one month to receive either testosterone or placebo, and all that simply does is bring the testosterone levels up to the normal range in just a much more rapid period time line than would happen naturally. Impact of Testosterone on Hormonal Studies And then see whether they're cognitive abilities improve. Okay. Now, if I were a prostate cancer patient, Dr. Higano, though, knowing that you wanted to lower my risk or control the prostate cancer by lowering the testosterone, then having some shot, if you will, of testosterone might be scary for me. Should there be any concern? Well, I think that's a natural impulse. However, if you just think about what happens in intermittent hormone therapy anyway, you know, while we're giving the treatments, the testosterone level is at rock bottom, as Dr. Cherrier mentioned, and when we stop the treatments, this is the intermittent part, eventually the testicles start producing testosterone again. That's just naturally what happens. And we didn't really talk about why one would do this, but I think if you think about it, for those who aren't familiar, it turns out that men feel much better when they have a normal level of testosterone, in general. They have better energy, their muscles are better, there's all kinds of things. And patients prefer to be treated with intermittent therapy. 4
So the idea is the testosterone level is going to go up to normal anyway. The testosterone that we give for one month, it's not a shot actually. It's a transdermal gel preparation, and it's measured carefully so that we don't overshoot, so we're only trying to get the testosterone level back to the physiologic, sort of normal ranges that a man would have if his testicles were at 100 percent at that time point. Dr. Cherrier, so is there a PET scan that comes into play looking at a man's brain activity as well? We did, we actually completed a study where we were looking at PET scans, and PET scans are nice because they are a measure of your brain activity. And in our previous study we did enroll men before they started their treatment, and we obtained a resting glucose PET scan, and then we also rescanned the men after they had been on androgen deprivation for a nine-month period. And we did see changes in the treatment group, and we're hoping that at some point we can repeat that study and then also look at the off-treatment period. All right. I've got a whole bunch of questions. We're going to take a quick break. When we come back we're going to ask our clinical investigators as they study cognitive abilities and effects of hormonal medicines in prostate cancer, really, what do we do with this knowledge we're gaining so that men can feel cognitively stronger yet fight the prostate cancer. We'll be back with more Patient Power right after this. Welcome back to Patient Power sponsored by the Seattle Cancer Care Alliance. So if you are a man who has been treated with hormonal therapy for prostate cancer, well, maybe you got hot flashes, no fun, maybe you had mood swings, and maybe you had trouble remembering things or maybe you like to build stuff in your shop down in the basement and it just was harder. Well, the evidence is showing up that hormonal therapy may affect certainly your cognitive ability. So as we're learning this from studies, and we have two clinical investigators here in Seattle who teamed up on all this, what do you do with the information? What do doctors do differently, or do we explain, manage expectations for patients when we talk about side effects of therapy. So Dr. Tia Higano has been involved in this for so many years as a prostate cancer specialist. Dr. Higano, do we start to do anything differently because of what you're learning? Yes. I think that what this information has allowed us to do is first of all validate some of the complaints that patients and their spouses have had for many years. And secondly, as you suggested, we do need to mention this before we start therapy so that there's some realization that this could happen. I don't think we want to scare anybody with this information because, as Dr. Cherrier mentioned, 5
this kind of problem does not happen in every single patient. One of the things we're trying to do is understand is there a specific type of patient that more of these problems happen in. Why does one guy have a lot of problems and the next guy have none? And combining the information I think from our past and current studies with some of the imaging studies may ultimately help us understand that. And long term what we want to get at is interventions that will help individual patients with certain aspects of whatever problems they're having with their cognition. Now, I mentioned about the mood swings and other areas. Dr. Cherrier, are you going to get to that as well? Irritability? I mean, it sounds like testosterone, we're talking about if you have a proper level of testosterone you just feel better, so are we going to look at the other things that are affected too? Absolutely. In fact, that's one of the things that we're trying to do better in this current study that we're performing right now is to get more precise and accurate measurements of mood and other quality-of-life factors that we think can without a doubt impact cognition. As you likely know, one of the most common symptoms that people report in going through various treatment regimens is increase in fatigue, and we know that has a huge impact on cognition as well sleep changes and mood changes. And sometimes those can affect your expectations or your experience of how you're performing, which is why we want to get that aspect of it along with the objective measurement of performance. So those two together really give us complementary types of information. But that's definitely one thing that we've added to the current study so we can really better appreciate what are some of the other changes. We certainly know from not even in the cancer literature but in the literature looking at men who have various disorders that render them to have low testosterone levels, and when they go for testosterone replacement in the old days it used to be almost exclusively injection and with injection you get more variable levels. And those men without a doubt would report increased irritability, loss of energy, like Dr. Higano was describing, in the few days leading up to when they would get their injection again, and that's because that's the point at which their testosterone had returned to almost zero again. So we do have some information from other areas that certainly corroborate what the men receiving androgen deprivation therapy are experiencing. Making Cancer Care Tolerable Dr. Higano, so the whole name of the game in cancer care is always cure the cancer, and if you can't, beat it back and keep it beaten back or beat it back for a really long time. I think most of us patients have understood there are side effects, but it seems like there's a very growing area of research now to try to make cancer care more tolerable, I guess. Is that right? 6
Oh, that's the name of the game, really. I think that has been our thrust really for many years because looking at cognition is one aspect of androgen deprivation but then there are other aspects that you and I have actually discussed in other programs looking at bone mineral density, muscle strength, weight gain, all these things that are side effects of androgen deprivation. We really have to try very proactively to prevent some of these negative side effects that can affect our patients because we're aiming for, if we're going to save you from prostate cancer with our therapies, we also want to save you from some of the side effects of the treatment, and we have to pay attention to those when we're using androgen deprivation. All right. Now, when I think of hormones, we're talking about androgen deprivation, but when I think of hormones I also think of other cancers, like estrogen in women. Correct. So, Dr. Cherrier, are we going to study that? I mean, could there be a parallel here at all? There can be because of course when you have a loss of testosterone you also in men have a loss of estrogen as well. So in fact the same mechanisms that we believe there's a link with estrogen and cognition in women there's also a fair amount of evidence to link estrogen actions and cognition in men. So we find it very interesting that this may be in fact one of the mechanisms rather than testosterone that may be driving these cognitive changes. Chemo Brain and Side Effects of Cancer Drugs All right. Now, I for my leukemia didn't have any hormonal therapy, yet I use this phrase "chemo brain" that we cancer survivors in blood cancers, we use this all the time. So will we get there too, that there might be just certain drugs that have more of that side effect on our ability to think clearly? Absolutely. In fact there are some studies ongoing now that are looking at that in animal models, where they're taking some of the chemo regimens and looking at mice or rats and giving them some of the cognitive tests that are appropriate, you know, for mice and rats and looking at those chemo regimen effects on cognition in animals. And there is definitely some indication that there are effects on cognition. 7
Of course the big question there is how long do these effects last, and are they permanent. There is some encouraging research certainly by a colleague of ours, Dr. Karen Syrjala, in which looking out in transplant patients that if you look out five years past their treatment that there continues to be some recovery. So I do want to say that I think that's where we need to go, is we need to be following patient for longer so if there is recovery it may be five or ten years out but that there's hope that you'll continue to improve. Dr. Higano, so you started by talking about the couples who come to you, and the wife says, you know, he's forgetting everything and he can't do some of the things he did before. So how are you beginning to talk to people now? So you're managing expectations, and if they've been married, you know, 30, 40 years and they have their idiosyncrasies, but the wife is worried that the guy, you know, not only is he fighting cancer but he's going downhill for good, what do you say? Well, luckily, honestly, we don't usually have that scenario where it's so severe. As a matter of fact usually there's kind of a question mark. Well, like, was this really going on before but now it's a little bit worse? So most of the time, every once in a while there is a severe situation, I'll get back to that, but usually it's just more of the same and only more so. And the first thing is to again explain and validate these observations that, yes, this is consistent with what we've seen in our studies. And depending on what this individual's problem is, that's where we're lacking on information on whether interventions such as certain brain games, you know, will it help you if you do a lot of crossword puzzles or Sudoku and so on. We don't know the answers to that, but certainly there is no reason to think that we couldn't use some of the strategies we use outside of the cancer setting for improving specific cognitive domains where certain functions need to be strengthened, if you will. Now, you mentioned you wanted to point out maybe a more severe case and what you do then. These are extremely rare, and we don't always understand those. And, honestly, if I had a patient who, where his clinical situation was not life or death, you know, do we really need to give androgen deprivation, my approach would be to stop the hormonal therapy if it was really that bad. And in fact we have done this where we would see is there recovery that's consistent with the increase in testosterone and parenthetically, as Dr. Cherrier mentioned, estrogen levels, or not. Because sometimes what we've found is this deterioration is true, true and unrelated and actually was some ongoing process that was happening that had no relationship to the androgen deprivation, you know, because it didn't get better once we stopped and we were at a normal testosterone level. 8
Well, it's a fascinating area. So we mentioned there's a new study going on. How can people get involved, Dr. Higano? Well, we have a contact person that we can put on your website, and we will screen people. Actually, Dr. Cherrier works with Tom, Erickson, who does all the screening. And if patients are willing we'll get them enrolled right away assuming that they're eligible. Tom will actually travel if necessary to do some of the testing that's required because we're trying to minimize the problems that patients might have coming from long distances. So that's how motivated we are to do this research. Yeah. And I'd just like to kind of also emphasize the points that Dr. Higano was making which is that's why it's so important that we get a pretreatment baseline because it may be the case that these problems are preexisting. And so we often get calls from people who will say, you know, I'm on hormone therapy now, can I be in your study. And although we'd love to have everyone involved that way, it's just for us to do good science we really need to capture people before they start their treatments. How about this? Maybe for people, like my dad used to play bridge, and he did take hormonal therapy, it would be great to say, Max, let's play bridge with you, then you're going to start your hormonal therapy, and then I'll come by your house and play bridge every month. He would have loved that. So just work out your strategies. Well, thank you for explaining this, and I think it really validates what so many people I'm sure have thought, but it's subtle usually and you just don't know. And then also for both of you your commitment to helping get the answers. And maybe then better treatment approaches that can minimize this for men and then men and women with other cancers as well, that would be terrific. Thank you for what you do, Dr. Tia Higano. Thank you for being with us once again. You're very welcome. And, Dr. Monique Cherrier, thank you. We'll have to talk another time about all your other memory research as well because as we all get older whether we're cancer patients or not, we're thinking about that all the time. Absolutely, yes. I'd love to talk with you more. 9
Okay. Well, thank you both for being with us. This is what we do on Patient Power. Thanks to the Seattle Cancer Care Alliance for working with us as we do this month after month. And, as always, remember, knowledge can be the best medicine of all. I'm Andrew Schorr. Thanks for joining us. Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, 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. 10