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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston. And it's a pleasure to welcome today, Dr. Sarah Psutka, who is an Associate Professor of Urology at the University of Washington's Seattle Cancer Care Alliance. Sarah is very interested and dedicated to research when it comes to many things to do with bladder cancer. And she presented this excellent talk at the recent Think Tank that we had, which was virtual, unfortunately, that talked about how to best perform perioperative optimization for patients undergoing radical cystectomy. And she is taking the time today to join us, the audience, and share some of her insights. So Sarah, with that, the stage is yours.

Sarah Psutka: Thank you so much Ashish, and it's a real pleasure to have the opportunity to share our work here. I'm going to focus actually on what was the impetus for our breakout section at the Think Tank and go through how we as a community are starting to think about optimizing patients who are undergoing radical cystectomy starting way before when the patient actually comes into the operating room. So with that lens, I'm really going to focus here on pre-operative optimization interventions to enhance outcomes for radical cystectomy. And these are some of my funding disclosures.

So the problem, which is not a surprise to anyone who is listening to this is that radical cystectomy is a highly morbid procedure. We know that complications depending on how we classify them occur in anywhere from a quarter to nearly almost every patient who undergoes this surgery. And complications can be loosely defined as some untoward event, but the point is that there is a high rate of readmission, high rates of re-operation, a lot of patients require ICU admission, a lot of these patients can not be discharged directly back home, and there is a not-insignificant risk of mortality within the short term after the surgery.

Most complications happen early. And whether we do this open or robotic, complication rates, as highlighted in the recently published RAZOR trial are relatively similar. And even with the widespread adoption of ERAS protocols, we see that there hasn't really been much of a shift in our complication rates.

So when I think about where can we start to intervene, we have several windows of opportunity to improve outcomes in this patient population. Certainly enhanced recovery after surgery protocols are critical to using data-driven methods to improve and move the needle reducing intraoperative risks and in-hospital risks. Certainly cancer survivorship programs that are formalized and again, data-driven can improve outcomes in early and late recovery, but I want to think specifically about how we can actually move the needle earlier on.

So I think about major windows of opportunity here both in how we risk-stratify patients and then in this sort of burgeoning field of rehabilitation, which is kind of where we intervene before surgery to get patients ready for surgery and as fit for surgery as we can. So I'm going to highlight three potential windows of opportunity or strategies focusing mostly on personalizing risk stratification and then pointing to a couple of key practical pragmatic nutritional interventions and highlight what is really an exciting field that has kind of taken off, which is exercise and fitness interventions.

So classically, when we think about how we risk stratify patients with bladder cancer, we think about things like chronological age, their burden of comorbidities, nutrition, performance status, and there are some really nice, very detailed surgical risk tools such as the ASA Score, which is ubiquitously used, and more detailed and more statistically robust tools that have been developed such as the NSQIP Risk Calculator.

But the truth is it's hard to estimate individualized risk, and that's because many of the tools that we use right now perform variably across the outcomes we care about in cystectomy patients. They demonstrate low specificity, and they are not granular enough sometimes, and actually, they can be hard to reproduce across different patient populations. So what do we fall back on? We fall back on the eyeball test, which is a gestalt impression by a physician of the fitness of that patient for a major intervention. The issue is this is based on experience. It's hard for us to teach, it's actually very hard to reproduce and there is pretty good data that physicians are just not that great at actually estimating how perhaps long someone's life expectancy will be and how well they are going to do with the variable treatments.

So I want to talk a little bit about some novel ways that we can assess perioperative risk. And the first is by using the construct of frailty. Frailty is a medical syndrome that has gained increasingly wide utilization in our field that has multiple causes and contributors as you can see here. It is characterized by low strength, low endurance, and decreases in physical function, and it increases vulnerability to bad outcomes. There are a lot of different ways that we can measure it. There are multiple different validated metrics, different phenotypes, different staging scores, some of which you can utilize administrative data, some of which are performed with geriatricians in the office. This is a visual tool, the Clinical Frailty Scale, that actually performs just as well as some of the more robust and granular frailty assessments such as the Canadian Study of Health and Aging Frailty Index. But essentially we are trying to get at understanding a patient's innate vulnerability to poor outcomes.

And a really nice study from the USC Group demonstrated that first of all, depending on how you measure frailty, the prevalence of frailty in radical cystectomy patients is somewhere between15% and over half. And furthermore, frailty is strongly associated with short-term adverse outcomes, including complications and serious complications. And so the authors here recommended that all elderly patients should have a frailty assessment before undergoing radical cystectomy. But here's the problem. The issue is that one, as I just said, there's a lot of different ways we can measure frailty, and two, frailty is dynamic. Someone's frailty level, whether they are robust, prefrail, or frail, may vary in where they are across the episodes of bladder cancer care.

And so another tool that is gaining wider... and this is actually a specific area of my research interest right now, which is utilizing comprehensive geriatric assessments in how we evaluate older patients' risk as we are getting them ready for treatment for bladder cancer. These are multidimensional assessments that identify potentially modifiable risk factors in patients. And really what we are trying to get at here is understanding, not chronological age, but physiological age and specific vulnerabilities that we can then target. And it's a multidomain assessment that looks at things like physical function, how severe the disease burden is, but also their burden of competing comorbidities. It looks at mental health and cognition, and then it also looks at the support networks that our patients have. And it's highly specific.

So a CGA will identify vulnerabilities in patients who have completely normal ECOG performance statuses and ASAs, as you can see here by some of the statistics that I have down here. And so it gives us a little bit more insight into potentially actionable targets that can move the needle for our patients. Surgical studies that have been published to date show CGAs when we use them in surgical populations, we can reduce risks of complications, delirium, length of stay, and other adverse outcomes. And probably one of the most important outcomes is that patients who undergo a CGA as part of their n-hospital care are more likely to return home and be living in their home independently up to a year afterward, which is a highly salient outcome of interest for a lot of these patients.

And at this point, CGAs are considered important and relevant and they are actually incorporated in all major international cancer guidelines saying that patients who are older generally over the age of somewhere between 60, 65, or 70, depending on the guideline, should receive this geriatric assessment to be screened for potential vulnerabilities that can be looked at. Now, the issue is that they are not used very widely. And actually, to date, recent studies suggest that only about 6% of surgical oncology clinics actually utilize the CGA.

Two really nice recent papers have been published just within the last year that have shown though that CGAs can be administered in a bladder cancer clinic. These are papers from Memorial Sloan Kettering and then from the UNC Group showing not only can we do CGAs in practice, but they can also identify key vulnerabilities and deficits in up to half of the patients as seen here from the Memorial Sloan Kettering group.  And higher accumulated geriatric deficiency scores are associated with adverse outcomes such as ICU admissions, mortality, and discharge to places other than home.

What's really interesting, and this is from Dr. Smith's group, is that they noticed not only did they find impairments in up to 78% of patients, but they noticed a significant decline in these in functional and nutritional assessments within the first month after cystectomy, but then they did notice that things got better over the following time. So these are dynamic assessments that can be implemented at different points in care and identify vulnerabilities that we can potentially target across the care spectrum and across episodes of care, again, potentially improving outcomes.

We at the University of Washington performed a prospective study over the past year that we will be presenting in much greater detail at the upcoming Society of Urologic Oncology that enrolled 94 patients in just over a year in whom we performed these really detailed assessments. These can be done both in-person and in telehealth. What's interesting is it only took 18 minutes in the clinic to do the assessment that we utilized. And when we asked patients about the burden, the vast majority of patients said that they were not burdensome at all or were associated with minimal burden. And very few patients expressed concern about the burden that this assessment had on their outcomes.

Interestingly, we also identified some substantial vulnerabilities, including dementia in 3% of patients, significant risk of depression, and then also malnutrition which is an actionable target. And we also had built out our CGA with some novel assessments of things like body composition and psychometric capital and identified some interesting vulnerabilities and also sort of resilience profiles among our patients.

So the issue is now with your risk assessment tools, you've identified the problem, how do you actually modify those risks? And the truth is the whole point here is that we identify personalized risks so that we can personalize strategies to essentially move that needle and target those risks or target those vulnerabilities. So if we look across all of the domains of the CGA, there are specific targets or interventions that we can then implicate and utilize and resources that we can tap to help a patient get the services they need. And whether it's specifically just simply looking at their medicine profile and making sure that there aren't significant interactions between the drugs that they are taking and the anesthesia, looking at getting patients who have these mental health concerns into psychiatry to try to manage that, or looking at optimizing comorbidities and getting, for example, a geriatric medicine internist onboard in that care, there are things that we can do that can hopefully get patients to a position where they are going to come into surgery in a better place than they were when we first diagnosed them.

Malnutrition is a key problem in the bladder cancer patient population. And a lot of data supports just how significant hypoalbuminemia and malnutrition are in terms of predicting adverse outcomes in patients undergoing radical cystectomy. And really malnutrition is sort of one early step on the continuum towards these other much more aggressive negative predictive factors, including precachexia and then sarcopenia, which is ultimately very severe deficits in skeletal muscle. Of note, we and others have shown that sarcopenia is independently associated with early adverse outcomes as well as short-term mortality and long-term mortality, as well as cancer recurrence in these patients. And so we think that these are important risk factors to identify largely because they are potentially modifiable.

Importantly, at this point, neoadjuvant chemotherapy is a key part of our armamentarium against bladder cancer in the radical cystectomy patient population. And we are trying to get more and more patients who are capable of getting through neoadjuvant chemotherapy through that in anticipation of going through ultimately consolidative surgery. Interestingly, we and others have shown that if you give patients platinum-based chemotherapy, the vast majority of patients actually lose muscle mass as well. And so there is the potential here where we are actually reducing physical function as well as nutrition and lean muscle mass in anticipation of a surgery that we know is going to be very strongly impacted by that baseline risk factor.

This was a small patient cohort that we looked at in 26 patients at Northwestern University and it showed that in 110 days between starting and stopping chemotherapy before cystectomy, patients lost an average of 6.4% of their skeletal muscle index. And then in a larger study that we haven't published yet but we're about to present at a meeting coming up, with 170 patients, we actually identified a relatively similar trend in terms of muscle mass and noted that muscle mass in both, the muscle mass at the beginning and after chemotherapy and the absolute change is associated with long term survival in these patients.

So what can we pragmatically do about this? Muscle mass loss is something that we know is an actionable target. It's something that is modifiable, and it can change through episodes of care. Importantly, it's something that is affected by both physical activity and nutrition. The ESPEN guidelines for patients with cancer who are undergoing therapy suggest that we should make sure that these patients are getting adequate nutrition and they give specific recommendations based on the patient's weight at baseline. But also I think protein supplementation is an easy-to-implement recommendation that most patients can adhere to. But interestingly, patients with cancer need a lot more protein than most patients in this age group and demographics specifically receive. So I think just having a heightened awareness of this, and if patients are not getting this kind of nutritional supplementation at baseline, identifying that and getting them to referrals, to nutritional dieticians are really critical to making sure that they have the resources they need and the education they need to be thinking in a preventative fashion or a prophylactic fashion about optimizing their diet.

A recent really well-done scoping review showed that the main recommendations that are pragmatic and really successful in this patient population not only are making sure patients are getting enough calories, specifically ensuring that they are getting enough protein, but then moving towards the whole concept of immunonutrition. And I want to highlight here a really excellent SWOG study that is going on, SWOG-S1600, the PI is Dr. Jill Hamilton-Reeves, looking at immunonutrition supplements in the perioperative setting with an eye towards reducing perioperative complications and optimizing outcomes, and maintaining muscle mass in patients as they're going through these therapies. And also I think that both the AUA guidelines and this recent review really highlighted the importance of doing these formal nutritional assessments and really talking to patients in detail about their nutrition as they are getting ready for surgery.

The other big question that has been sort of a hot topic of late is, can we do exercise interventions? And the answer is yes. And I want to highlight here a great trial that was done, headlined by Dr. Kaye with the PI being Dr. Jeff Montgomery. They performed a Phase I and II clinical trial where they enrolled 54 patients in an exercise intervention in the four weeks before radical cystectomy. They showed that not only is this feasible and the vast majority of these patients were able to complete greater than 70% of their exercise sessions, but It was also safe. There were no adverse events, and it was effective. Patients actually maintained their muscle mass and noted an increase in functional outcomes while going through this therapy. And interestingly, there were significant increases in quality of life. So I think that this is sort of the beginning of... we are starting to see the beginning of a wave of really thinking about how we design these exercise interventions or exercise prescriptions for our patients to increase their fitness for surgery in really validated ways.

And this is a paper that I worked on with a number of collaborators recently thinking a little bit about... reviewing the data for what's been done in bladder cancer patients and genitourinary cancer patients who are undergoing these kinds of exercise interventions. And what we tried to highlight here is when we think about prescribing exercise, we really need to draw on the expertise of our colleagues in PM&R to make sure that the exercise prescription is therapeutically valid for our patients so that we are designing research or we are designing exercise interventions that are feasible and safe, but also we're really going to kind of get at what we need in the time when patients are on these exercise programs. So making sure we're thinking about core strength, balance, avoiding falls, things like that.

There were about 10 exercise trials that have been done in GU Oncology at the time when we did this analysis. The content validity is sort of variable across those, but it's something that I think a lot of people are starting to think about and really bringing the expertise of our PM&R colleagues and our cancer survivorship colleagues into advisory roles on designing these trials, which is going to be really important moving forward.

So just to kind of take a step back and conclude, we really want to think about how... If we want to move the needle for patients undergoing radical cystectomy, we really have to start long before we get into the operating room. We want to think about how we risk stratify patients using data-driven methods in order to inform what additional testing is necessary, what presurgical interventions we can invoke to improve physiologic strength and resilience. Nutrition and exercise are probably two key ways that we can do this, but it's going to be ultimately a team effort with the goal of getting to the point where we can get patients across the finish line a little bit more easily. So with that, thank you very much for the opportunity to present some of this work and highlight some of the great work that is being done in this field.

Ashish Kamat: Wow, Sarah, that was kind of a whirlwind through the whole prehab paradigm for bladder cancer patients. It was great. Thank you so much. You presented a lot of data and a lot of this is work that you have been involved in yourself. ERAS per see is now almost standard in most places that are doing these number of radical cystectomies, but in some centers, and especially in some countries, it's still looked upon as this pseudoscience that may not actually help their patients because their patients stay in the hospital 7, 10, 14 days as a matter of routine, and going home early is not "relevant" to them. I personally have my bias against that argument and I think ERAS is still important for all patients, but what do you say to those critics when they say, well, our patients are in the hospital 10 days anyways. Culturally, they are not going to go home. Why do we need to do all of this?

Sarah Psutka: Well, I think that ERAS is about the... so again, enhanced recovery after surgery (ERAS) protocols are data-driven point-by-point checklists that are targeting the sort of... again, it's a multidimensional evaluation and it is truly an evaluation and tool that we use to improve outcomes for these patients. If the length of stay is not maybe potentially relevant, the ERAS pathways have been associated with reductions in complications and functional recovery reduction, and ICU admissions. The whole point here is getting patients through the recovery as easy as possible, even if patients are going to stay in the hospital until they are kind of fully recovered.

And certainly, I've operated and done cystectomies in other countries where the patient's stay was many weeks because that was sort of the norm there. I think we can still invoke some of the key protocols that are important to ERAS, things like how we think about pain management, so invoking a multi-modal pain pathway that is not heavily narcotic-based. We can improve outcomes that reduce gastrointestinal complications, get people back to PO nutrition early, which we know is a key part of getting folks through the recovery after radical cystectomy. We avoid fluid overload. There are so many potential benefits. So even if the length of stay is not the outcome that potentially is most salient for that patient population, I'm sure complications are universally important.

So I think that's one of the key reasons why I certainly rely heavily on my ERAS protocol and also we are always thinking about how we can improve it and make it more responsive and more appropriate. And really a lot of this risk stratification work we're doing is with a goal of augmenting that ERAS pathway and bringing it into the pre... some of us have jokingly called it pre-ERAS. You're bringing this in advance of saying, those just a couple of weeks before surgery when you start doing the early work in ERAS, the counseling expectation setting, and the early pre-nutrition that many ERAS pathways invoke.

Ashish Kamat: And absolutely, that's a perfect segue to the point that I was going to make. So I completely agree with you. And many of the points that you raised could be the topic of another similar discussion that we call you back to participate in, but this whole concept of getting the patient involved in his or her care early on and helping them through the CGA, and helping them to defer the assessment and nutrition supplementation is just I think an extension and reflection of our understanding and recognition of the fact that it's teamwork. The patient is an integral part of this whole team. In fact, the patient is the critical piece of the whole team.

The World Bladder Cancer Foundation just launched its global effort recently. And I was fortunate enough to be part of that inaugural effort in getting patients across the globe and the nurses and their caregivers, everyone involved in the care leading up to the days to cystectomy. So I think this work that you are doing is really phenomenal. I really applaud you for highlighting this and for doing all the work that you've done over the years and for leading the breakout session at the Think Tank. Where do you see this going? In other words, what are some of the next steps that came out of the workshop or of the breakout sessions that you guys led at the Think Tank?

Sarah Psutka: Well, I think that in terms of... I feel like I've kind of taken a real step back with a lot of this work. People are designing these trials now to see how we can improve outcomes. I think a lot of the work that I've been doing has actually been on kind of trying to take a step back and maybe think about defining the problem. A lot of times we don't necessarily... so for example, in the body composition work,  we didn't necessarily know the prevalence of patients that met the key definitions for sarcopenia, which we know is an adverse risk factor. We hadn't really defined what that was until the last couple of years. And now a lot of people are doing some great work in this space and doing high-quality composition studies.

If we don't know what these measures mean, it's hard to know what changing them is going to do to outcomes. So I think I've been focusing a lot on trying to figure out what tools, how we can design tools that are going to be easy to work within our clinical practice because they have to be easier or nobody is going to use them. They have to be resource economic and then they have to be meaningful. They have to have content validity and they have to actually matter to the outcomes of our patients. So I think that is what I have personally been working on, is sort of defining what elements of the CGA are salient, and is it feasible to even do this in the clinic?

The next steps though here are really designing these comprehensive pragmatic interventions that are based on all the great data that is being generated by people who are studying how nutrition and exercise and physical function, and actually, I think bringing a lot of... I think one thing that a lot of people are starting to recognize is the incredible parallels and the opportunities to really bring what is standard medical practice and geriatric medicine, bringing that into our geriatric oncology, our bladder cancer practice. Given that the median age of most patients with bladder cancer is 73, we are talking about a patient population that is highly at risk, has a high burden of comorbidities, has a high burden of frailty and sarcopenia.

So we kind of need to be using those words and that language and the medical principles that are utilized in high-quality geriatric medicine practice to optimize these patients' function and then their outcomes. So I think that is a big part of what we identified in the Think Tank breakout as the next steps in bringing the patient perspective in and thinking about what are the relevant outcomes, not maybe just thinking about the oncologic outcomes that many of us track with complications. And this goes to your question earlier, Ashish, about the ERAS protocols. Is the length of stay salient or is it actually... can I get home by myself without a walker?

And there is pretty good data that was generated early in the 2000s by [inaudible 00:27:07] and his group that showed that the length of survival may not be the relevant outcome for a lot of older patients with advanced malignancies, it's the quality of life during that time. So again, a lot of this work is we need to understand its implications for this kind of hard clinical endpoints, but we also need to understand the more classically defined geriatric outcomes and how they dovetail with all this.

And I know I'm talking a lot, but the one other thing that you said that I just think is so important that I think about a lot when I think about my practice is kind of bringing the patient onto the team and how patient-centered and personalized risk stratification and then these patient-centered personalized interventions engage someone around what matters to them. And one of the hardest things about a cancer diagnosis is that it takes away control from patients or it can. And I think a lot of patients describe that sort of feeling like the carpet's been ripped out from underneath them when they get these diagnoses. And a lot of these interventions are very positive life changes that patients can do themselves.

And so it sort of reassigns, it gives them back some control and they can focus on good nutrition, they can focus on physical activity. And they are really meant not only to just move the needle on clinical endpoints but really improve how they live their life as they're going through. And this is the survivorship piece, like surviving the diagnosis, the treatment, and then the recovery from these treatments. So I think that those are all really important points. And I love the fact that the field is focusing on some of these issues at this point, and I'm excited to see all the good work that is being done in this arena as it matures over the next couple of years. I think we are going to see some really exciting new tools that we can bring into practice.

Ashish Kamat: I think so. And again, with folks like you that are corralling the skill forward and getting folks to work together, I think we are definitely going to see a lot of advances. You and I could chat on forever, but obviously, in the interest of time, we have to kind of wrap it up. If I were to ask you to leave the audience with two key things that they can implement in their practice right now, what would you tell them?

Sarah P. Psutka: I think the first is to really get a sense of a patient's physical function and where they are at. I think asking questions that are directed at really defining kind of how a patient lives their life beyond just the typical sort of performance status questions, I think that's really important. And that is certainly where I've been able to identify real vulnerabilities very quickly. And a simple question is just have you fallen in the last month? And then the second thing I think that is really easy to do and its guideline-directed is talking to patients really strongly about their nutrition because it is something that will make them feel better and especially as they are going through chemo. The moment of diagnosis is an actionable moment.

And I think a lot of people are pretty receptive to things that they... to sort of making potential changes that they may have been pre-contemplative about at that point previously. This is a teachable moment where you can say, here are a couple of simple things that you can do that are going to help you get through chemo, help you get through surgery. And things like protein supplementation and hydration, stuff like that are basic, key things that everybody should do. The more detailed assessments we are working on, and we're going to try to find ways to, I think, make that easy for people to do, but at the very basic, the two things that everybody can do is really get to know their patient and where they are at physically and then encourage them to make some positive changes as they start to think about getting ready for these treatments that they are going to have to go through.

Ashish Kamat: Thank you again so much for taking the time and spending it with us. Hopefully, we'll get a chance to see each other in person soon, maybe in 2022. Take care.

Sarah P. Psutka: You too. Thank you so much. (silence)