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Zachary Klaassen: Hi, my name is Zachary Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I am delighted to be joined by Dr. Sarah Psutka, who is a urologic oncologist at the University of Washington. Sarah, thanks so much for joining us today.

Sarah Psutka: Oh, thanks, Zach, for having me. I'm so thrilled to be here.

Zachary Klaassen: So, we are going to discuss a very interesting topic. You guys had a phenomenal BCAN Think Tank, and you discussed unveiling innovations in cognitive resilience during bladder cancer care with prehabilitation and rehabilitation. So, why don't you tell our listeners about your guys' discussions that you had at the BCAN Think Tank?

Sarah Psutka: Sure. Well, so this was, I would say, a continuation of a discussion that we started having about four years ago. So, four years ago, we started talking a lot about just the idea of how do you start to think about risk in patients, and then you identify the problem, and it moves to mitigating solutions, right? So, how do you mitigate the problem? So, we moved from really deep dives into risk stratifying across kind of all of the different parameters, got into a lot of the work that I've been doing in geriatric assessments. We've talked about nutrition, we've talked about physical function assessments, but one theme that kind of kept coming up out of the discussions was this whole concept around the impact of, one, having cancer, and two, going through cancer treatment on how our brains function.

And it manifests in so many different ways. And I have a couple of slides that I can pull up and show you, but this was sort of the continuation of doing this deep dive into how do we optimize candidacy for therapy and optimize outcomes with therapy, but really thinking about the impact of cancer treatment on the brain. This is just kind of a summary of some of the things we talked about. So, first of all, I had the honor of running this Think Tank with two really great people. So, Hannah Hunter is a physical medicine and rehab doc who I do a lot of work with. She is our Director of Cancer Rehab at the Fred Hutch Cancer Center and is somebody who I send my patients to for personalized exercise prescriptions. She also is the person that I've run this kind of rehab/prehab kind of Think Tank breakout session with the last couple of years.

David Shepard's a new addition to our team, and it was just awesome to work with him. He's a neuropsychologist who has been doing a lot of work at the Hutch at our cancer center in terms of really kind of deep diving into these questions of how do we handle cognitive changes associated with cancer diagnosis and cancer treatment, and how do we think about helping patients deal with those better? So, this is what we kind of came up with. So, the first thing I think that's really like an under-recognized problem in our field is just how much surgery affects the brain. And it's something, especially I know, Zach, you and I have kind of similar patient populations; we take care of a lot of folks who are older, who have a lot of other medical problems, and asking them to go through a general anesthetic, whether it's for something, a big operation like kidney surgery, the radical cystectomy, you name it.

But even for the TURBTs, the short cases—maybe it's only 20 minutes of anesthesia—some of our patients, it takes them weeks to months to recover from that. I am increasingly seeing—it's funny, I don't think I'd always been taught to ask patients about that, but I've recently, through my work in geriatric oncology, been spending a lot of time talking to people about how they kind of feel like they're functioning in the world around them. And this is a constant theme that comes out. So, basically, we know that any general anesthetic is associated with a risk of up to about 14% of transient postoperative delirium, which can be incredibly devastating and associated with really bad outcomes such as not only aspiration, loss of consciousness, falls, all the things that can happen related to those sorts of events. They definitely delay recovery, and they can increase length of stay.

They certainly impact the patient experience of recovery in terms of orientation, attention, their ability to make good judgments as they're recovering. And just that delirium piece is associated with a massive increase in the risk of complications, mortality, and as a matter of course, economic burden related to the treatments that we're asking our patients to go through. The other thing that I think is the other risk here that is, I would say, really under-recognized and definitely not talked about enough, is the risk of persistent postoperative cognitive dysfunction, which is actually, in folks who are going—the risk is higher in cardiac surgery, which is why we sort of separated it out here—but in non-cardiac surgery can affect up to a third of patients, and the risk for postoperative cognitive dysfunction after a general anesthetic goes up with age. So, this is kind of laying the basic line here, and we've really moved away.

When I started doing a lot of this research, I was thinking a lot about assessing for frailty and trying to understand sort of physical function deficits and how that impacted outcomes in cancer surgery. I've moved away from that language completely and really have started to actually steer towards understanding a patient's personal profile of what I call resources, which are things like physical robustness, cognitive resilience, psychosocial resources, but also their vulnerabilities, or their own risks, which may be related to the cancer but may also be related to multimorbidity, cognitive dysfunction at baseline, and physical deficits. And the reason being both resources and vulnerabilities are actionable targets. If you know what they are, you can make resources stronger; you can hopefully make vulnerabilities less.

I think one really key discussion that David led was the fact that as we have this growing number of cancer survivors, because we have a lot much more successful cancer treatments, we also have a lot of older patients with cancer who are survivors, we have a lot of patients who have cognitive impairment at baseline who are older, and now we have a lot of older cancer survivors with cognitive impairment. So, we are seeing a pretty substantial increase in the number of patients who are dealing with this problem, but it's also a major concern on the part of the patients. So, patients, if you ask them about what they're worried about, about half of patients will say that they're concerned about how their cancer is affecting their cognition. What's interesting is when you actually go to try to do an assessment to understand whether or not they're cognitively impaired using validated assessments, it's actually a much smaller piece of the pie that truly are impaired.

But the fact that 50% of patients are worried about this, I think that underscores the importance of the topic. And chemotherapy—we actually did a real deep dive in the breakout session on chemo brain, which is something that patients talk about a lot, and David did a really nice job of explaining the etiology of it and where it comes from and just how kind of insidious it can be. Generally, the cognitive impact of chemotherapy—any systemic antineoplastic therapy—patients do, if you screen them, will demonstrate some mild cognitive weakness. Now, interestingly, it may not be true cognitive impairment, but a lot of times it has to do with the cognitive burden of the treatment, and it can certainly affect everyday functioning in terms of their ability to actually complete the tasks that they need to, and it can impact executive functioning, but it also really affects things like just kind of fatigue and their ability to kind of get through every single day.

Even those patients who may not, again, screen positive on validated assessments of cognition, usually it goes away about a year after the patients who go through the acute stress of the treatment. But it's very common, and in some cases, it can persist for really long, long periods of time. And especially when you think about life expectancy in our patient populations, this can be something that's going to impact them for the rest of their life. Beyond the actual impact of an anesthetic or chemo on the brain, we also know that patients who are dealing with cancer have a lot of different things that generally can impact how their cognition works. And it's not only the treatments; it's not only the cancer and potentially brain mets—obviously, it's a very different story if we're talking about folks who actually have brain metastases and are going through active radiation to treat that or something of that nature.

But particularly the mental health—and this is something you know about better than anyone in our field—the mental health implications of a cancer diagnosis can impact how patients' cognition can impact cognition, patients' pain and pain medication, any hormonal changes that they're undergoing or the hormones they're taking. Certainly medications, anesthesia, chemo, radiation, but also really importantly, the distress of being a cancer patient, of going through therapy, of having this diagnosis, and the anxiety and stress and sort of what I think we're all becoming much more aware of—this concept of treatment burden, the work of being a patient—that can really impact cognitive functioning as well. So, just to kind of wrap up, we spent a lot of time at the breakout thinking about how can we actually mitigate the risks of cognitive changes related to both cancer and cancer treatment? And David broke this down into two big areas.

The first are what are called restorative interventions, and these are really—you can kind of think of it like when we talk about our exercise interventions to help patients who are physically frail become stronger. These are really cognitive interventions with the goal of strengthening the brain to reduce the cognitive impact. And it's all about improving and restoring your natural cognitive abilities. These are basically exercises for your brain. So, I'll just give you an example of a trial that has gotten a lot of press. It's probably one of the most well-known trials in the cognitive prehabilitation space. It's called the Neurobics trial. And basically, the intervention here was 10 hours using sort of a Lumosity-type tablet-based cognitive intervention, brain games that sort of strengthen and then train the brain and really kind of tax the brain using whether it's pattern recognition or some of the word games that we—or math games, things like that—to really get people thinking. And the key outcome here was the risk of postoperative delirium. Now, what's really interesting is that patients were sort of encouraged to use this intervention—it was a randomized trial.

Patients who were randomized to the intervention could use it for up to 10 hours. Most people only used it for about 4.6 hours. In the intention-to-treat arm, unfortunately, there was no statistically significant signal, but in the folks who actually used the intervention, there was a signal towards—of course, that's biased—but there was a signal in the per-protocol arm towards reduced risk of postoperative delirium with a much lower dose than the intervention had been designed to use. And Itay Bentov is an anesthesiologist who I have the fortune of working with in my role at Harborview Medical Center here. He recently led this really nice review article that I think is a great kind of introduction into the world of cognitive prehab, and specifically these restorative interventions for an edition that we did for EU Focus on prehab. And I think he goes through and explains how these interventions work and how much time is required and how they have sort of the potential to benefit our patients.

The other really neat area of intervention are really more compensatory interventions, and this is really all about the practical aspects of how can we help unload patients' brains from the work of being a patient. And it's really all about decreasing cognitive difficulty and, again, unloading cognition. So, managing specifically things like fatigue, anxiety, but also kind of taking a lot of the extra work out of daily life. So, David talks about how he works with patients around developing strategies to really make life a little bit easier and a little bit less cognitively intense. So, things like setting alarms to remember to take medications so you don't have to be thinking, "When do I need to take my next med?" So, having calendars to organize appointments that aren't in five different places or checklists all over the house, but kind of really getting organized and simplifying your organizational strategies to kind of get into routines that make it easier to do this work.

Even little things like having a central hub where you can always put your car keys. And of course, these are things that all of us can benefit from. What David specifically made reference to that I thought was really interesting was that these compensation strategies actually seem to work better in real time, in real life. So, something that I've started to talk to a lot of my patients about—and then you and I have before have talked a little bit about some of the work that we've been doing in prehab—really thinking about how can we expose patients to interventions before. And I've moved away from just thinking about surgery, but really before any medical treatment so that patients can tolerate the therapy better. And here really we're focusing on working on these modifiable risk factors to try to optimize patient status to improve candidacy for therapy, improve outcomes, and return to better baseline.

And I've spent a lot of time over the last couple of years focused on the physical and nutritional aspects of that, but we're really kind of getting into thinking about how can we move the needle on mental prehab or cognitive prehab. And these are now not new at this point, but relatively new ASCO guidelines on exercise, diet, and weight management that really talk about the benefits of exercise in patients who are going through active antineoplastic therapy. And a big part of one of the big domains and benefits that they really detail is how it improves things like fatigue, how it helps patients sleep better and rest better, recover better, and then also improves things like mental health. We currently, in our Get Moving trial, which we've talked about previously, are looking at cognitive outcomes. And then this is something, as we're designing new trials, we're really thinking about trying to incorporate more effectively.

And I think this has actually just become a real soapbox issue for me, which is that I think we had been really talking about prehab as kind of the thing that you do before a major intervention like a radical cystectomy or thinking about how do we bring this work into the realm of getting people who are going through EV Pembro, people who are going through substantial anti-cancer therapy. But the truth is, I would argue that pretty much everybody can benefit from a little bit of prehab, especially if we identify during the risk stratification procedures specific vulnerabilities that may be targetable. So, in my world, I've started to talk to patients who don't even have surgery on the horizon. Maybe they're in their survivorship period for non-muscle invasive bladder cancer, but they're falling a lot. I've been talking about getting them into PM&R.

The patients who are obviously getting ready for radical cystectomy, there's lots of areas where we can think about helping them get stronger, but I think that really there's potential benefit here in helping patients think about how they can kind of optimize their function across the different domains—cognitive, physical, nutritional—throughout cancer survivorship. So, this was just kind of wrapping up everything that we talked about, but it's really common to see this neurocognitive vulnerability in our patients. It's something that we probably don't talk about enough, but we should, I think, have a heightened awareness around. There's a lot of really negative impacts of cognitive dysfunction, and I think thinking about how we can pragmatically bolster cognition and unload our patients' brains, reduce fatigue, anxiety, distress, cognitive burden of cancer treatment may actually really be very beneficial in terms of helping them get through therapy more effectively and maybe decrease some of the toxicity of therapy.

And I think what we're seeing is there's pretty clear evidence that there's benefit to some pretty pragmatic strategies that everybody can do. These restorative retraining strategies are really interesting and I think are emerging as potentially very beneficial. And then the work that we do in other domains has potential cognitive benefits as well. So, that's where exercise and good nutrition—obviously, I say things that are good for the heart are often good for our patients who are going through cancer treatment. It seems that there's probably some pretty significant overlap with it in terms of the brain as well. So, I don't pretend to be an expert in this. David and Hannah were really the experts here. I helped to facilitate the conversation, but it's something that we're really thinking about how we can do a better job of bringing into our prehab work.

Zachary Klaassen: So, there's so many jumping-off points here, Sarah, and I think you and I could talk for an hour about all the implications. You put up a figure with so many factors in that bubble diagram that lead to these issues. And so just to touch on a few, I think you brought up a great point about the anesthesia. We often don't talk to these patients about the risk of a TURBT, and we hear this all the time, and moving on to the non-muscle invasive where we get the patients—they're in their 10th round of maintenance of gemcitabine/docetaxel, and it's just a struggle. They're struggling just to get out of bed, and often I think this is an interplay here. So, in your mind, tomorrow, how can we alleviate some of these distresses? Obviously, there's a ton of work that has to go into targeted interventions, but what should we be taking home tomorrow to the clinic that we can try to help our patients immediately?

Sarah Psutka: I think the biggest thing is actually giving patients the space to talk about their concerns about their cognition. It's something that we don't—I don't know about you; I wasn't really trained to talk to my patients about—but as I've started to sort of—it's the same thing as giving people permission to talk about whatever's bothering them: sexual dysfunction, financial toxicity, cognition. And it's really interesting if you actually ask, people will certainly open up about this, and I think it's clear that it's a very prevalent concern, but a lot of times patients may, one, not even be aware that they're concerned about it, or they may just feel like it's not the right place to bring it up.

The other thing I think is really helpful is really helpful to talk to families, because patients may or may not have awareness of their cognition and sort of how it may be being impacted by the therapies that they're going through. But it's super helpful to talk to a patient's partner and say, "Hey, have you noticed any changes? Is there anything you're worried about?" And it's amazing; this is actually something that I definitely have—I've had patients whose family members have brought up real concerns over their short-term memory. They'll be the ones who say, "The last time we did that TURBT, he really didn't seem like himself for weeks afterwards." So, I think it's kind of—the biggest thing is being aware that this is an issue.

Zachary Klaassen: Yeah. I think you brought up a good point, too. I mean, it's almost going back to med school. We have to be good listeners, and I think it's easy for us to go in and have a plan and bang through that plan. And the temptation is to get up and move to the next patient. But if we sit and we just listen for two, three, four, five minutes—maybe more if we have to—the point of listening and just the therapy of somebody talking it out, I think you mentioned it perfectly, that often alleviates at least some of the distress or the anxiety, and certainly this is multifactorial, but I think as we see these patients, especially the elderly patients, I think it's a huge, huge factor.

Sarah Psutka: Couldn't agree more. It's funny, right? I talk to my residents about this. I say, "The patients will tell you what the problem is. You just have to give space to listen."

Zachary Klaassen: To listen.

Sarah Psutka: It's amazing because they'll tell you exactly what's wrong, but it's also giving people space to talk about stuff that maybe they didn't know that they could talk about. Because it ends up being really meaningful if a patient has had really severe postoperative delirium that you didn't know about after they went home after TURBT. I'm thinking about a patient I saw in clinic today who just has—every time she has an anesthetic, she has a really challenging emergence that's frankly terrifying for her.

And so it means that I'm doing everything I can to keep her out of the operating room and doing things like biopsies in the clinic and fulgurations in the clinic for the cancer that we're taking care of, things like that. I can fix that. I can be responsive to that, but if I didn't know that this was such a major concern, I maybe wouldn't be thinking about it as much.

Zachary Klaassen: Absolutely. Congratulations on great work. I know that the Think Tank always has such good sessions, and we appreciate your time discussing today. And if you have a couple of quick take-home points for our listeners, that'd be fantastic.

Sarah Psutka: Absolutely. Well, I think just what we've just been talking about: think about how your patients' brains are being affected by the cancer and by the cancer treatments. I think giving patients space to talk it out can be helpful. Most of our cancer centers do have great resources for patients who are feeling that they're having these kind of cognitive effects, and I certainly am starting to really lean on our neuropsychology team. My colleagues who are geriatricians have also become great resources for me to start to think about how to protect my patients' brains as they're going through these treatments. And then I think I really like David's take-home point about the fact that compensatory strategies, which are really low-hanging fruit—they're very pragmatic, they're very easy, it's nothing fancy, it doesn't cost any money, and they don't take any time—they can be incredibly effective at unloading patients' minds so that they can be more effective. And so I think just bringing up those very basic things can be incredibly helpful.

Zachary Klaassen: Excellent. You've always been generous with your time on UroToday, and we thank you again for your expertise. Sarah, thanks so much.

Sarah Psutka: Thank you so much, Zach.