Read the Full Video Transcript

Leslie Ballas: Hi there. Thank you so much for joining. I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai Cancer Center in Los Angeles. I am pleased to be joined today by Dr. Kimberley Mak. She is an associate professor of radiation oncology at Boston University. She, with others, led a very interesting discussion at the Bladder Cancer Advocacy Network (BCAN) Think Tank this past summer, discussing quality of life for patients who undergo trimodal therapy. Dr. Mak, thank you so much for joining me today.

Kimberley Mak: I'm so glad to be here. Thank you so much for inviting me. Thank you again, Leslie. I'm so excited to share highlights of our breakout session. It really was truly a lively, invigorating discussion on the latest and greatest data on quality of life after trimodality therapy for muscle-invasive bladder cancer.

Many folks in the room weighed in. In addition to myself representing radiation oncology, we were delighted to have Mary Beth Westerman, a urologist from LSU; Kriti Mittal, a medical oncologist from the University of Massachusetts; and John Treffert, a patient advocate. John actually led things off by sharing his inspiring journey to date with bladder cancer.

He had actually worked in the development approach on therapy, so he sought a trimodality therapy treatment approach rather than radical cystectomy. While he fought the healthcare system for insurance approval, he actually ended up pursuing chemoimmunotherapy, which had recently obtained FDA approval and is doing really well to date on it.

That got us started on a great discussion about the side effects and quality of life considerations that might influence a patient's treatment decision and with an eye for the future treatments of tomorrow. Dr. Westerman then shared the latest data on salvage cystectomy, noting that the need for a salvage surgery continues to be rare after trimodality therapy.

The indication for the vast majority of cases is recurrent disease. She highlighted that quality of life tends to be improved in these situations compared to preoperatively, and that late complication rates are actually very similar to standard cystectomy complication rates. One of the enduring questions that remains is how do we know when salvage cystectomy might be beneficial in terms of quality of life after trimodality therapy?

As you know, there are different ways to measure how a patient is doing—objectively using urodynamic studies versus subjectively with our patient-reported outcome measures that measure symptom bother from the patient's perspective. We then discussed how sexual health is such an urgent, prevalent concern among our cancer survivors in general, but especially among those with bladder cancer.

The interplay between sexual function and quality of life is so complex, and we really don't have a great understanding of how bladder cancer treatments impact sexual health domains. Leslie, even your study, of course, that suggested that women have more interest in sexual activity than men after trimodality therapy. Certainly, women versus men, those are very different sexual concerns. We need so much more research on how bladder cancer treatments affect these domains.

Lastly, Dr. Westerman highlighted another hot topic: financial toxicity, showing that baseline financial toxicity is not associated with worsening financial toxicity during radiation, but that rural residents and hospitalization during treatment are associated with worse financial toxicity. We then reviewed the current data on quality of life after trimodality therapy compared to radical cystectomy.

Recognizing, of course, that there hasn't been a successful randomized controlled trial that compares the two modalities head to head. As of now, we know from studies like the one that, Leslie, you kindly highlighted that I was part of, that general quality of life is probably similar between the two treatment options, but that physical and mental quality of life likely favors trimodality therapy, as does the sexual function.

Though, as noted on the previous slide, there is limited data on sexual function after bladder cancer treatment, especially with regards to trimodality therapy. Adjustment to appearance and impact on life interference seem to favor trimodality therapy, as does the process of informed decision-making.

In terms of what might be similar between trimodality therapy versus surgery, it looks like urinary function and future perspective are domains that aren't clearly favored from one treatment choice or the other. Lastly, what appears to be a common thread is that bowel function is worse after trimodality therapy compared to surgery.

Turning to the future, Dr. Mittal discussed emerging treatment paradigms. In the domains of chemotherapy, immunotherapy, chemotherapy with immunotherapy, and novel agents in combinations, she highlighted that there are new ICD codes that help clinicians identify immunotherapy-related adverse events. These acute events can often become subacute or chronic events in the realm of immunotherapy.

She then pivoted to the discussion on how to measure quality of life and what available questionnaires are out there, noting that, as we all know, there are general quality of life measurements like the EQ-5D, but also cancer-specific ones that are for any patient with cancer. Then even more specific bladder cancer-specific questionnaires, then there are questionnaires focused on toxicity—so side effects of treatment.

More recently, there are more and more questionnaires that are focused on more specific subdomains like cost of treatment or the fear of recurrence. In more recent research, the latest quality of life measurements even look at things like treatment effects on hospitalization and recovery time, work productivity, and activity impairment.

Both Dr. Mittal and I work at safety net hospitals. We did have a lively discussion on real-world considerations when we think about our cancer patients. We know that treatment at an academic institution predicts for superior overall survival for patients undergoing radical cystectomy, but not for patients receiving chemoradiation.

The vast majority of patients obviously are not always able to go to an academic institution, or they may not choose to. Chemotherapy choices, Dr. Mittal points out, really depend on patient characteristics and provider preferences. What we see in a clinical trial might not be what is given day to day.

Ultimately, we had a great discussion on how vulnerable and underserved populations are really not adequately represented in clinical trials. Overall, we need to measure the real world, right? Routine patient-reported outcomes in clinical trials and not just in clinical trials. Future directions were obviously the next part of the discussion.

As we discuss the next steps and where we should move as a field, we need more prospective and comparative studies. The latest NRG study that's being developed, ARCHER, will randomize hypofractionated 20 fractions to ultra-hypofractionated five fractions of radiation. We're looking to decrease the number of treatments to help with patient convenience and some of those late toxicities in terms of financial or work-related impairments that we discussed on the previous slide.

As part of ARCHER, sexual function and financial toxicity are among the patient-reported outcomes to be measured. As we noted, we do want to expand patient-reported outcome measures beyond clinical trials by addressing health disparities, including diverse and underrepresented patient populations in our measurements of patient-reported outcomes.

The next wave of the future includes AI to help predict quality of life and using biomarkers to develop treatment-specific efficacy and quality of life prediction models. Ultimately, we need to make our patient-reported outcome measures easy, accessible, and routine so that we can help more people and learn more about our patients.

We know that monitoring patient-reported outcomes is associated with improved survival in advanced cancers. How can we get more information on our patients so that we can help their outcomes? One of the ways that we'll do that is by improving technology using electronic patient-reported outcome measures and electronic conversational agents that can help engage a patient and want them or encourage them to finish their questionnaires.

Ultimately, we learned by carefully listening to patients reporting their quality of life and symptoms that life could be a lot worse, but it could be a lot better too, and that's what we strive for each and every patient that we see. That was a summary of our discussion, and I'd love to talk more about it with you, Leslie.

Leslie Ballas: That does seem like a wonderful session. I'm impressed with all that was covered, and I can imagine that there was a lot of back and forth, and having a patient there is really a wonderful component to any discussion on these quality of life metrics. Kim, as you mentioned, I do have a particular interest in sexual quality of life in patients after TMT.

As we know, women are underrepresented in the bladder cancer—women have bladder cancer diagnosis a lot less commonly than men. I think that there's been a lack of understanding of women's sexual health because of the small numbers of patients, women that get bladder cancer and women that get TMT. I'm wondering, did you guys at all talk about differences in either quality of life domains or how to adequately capture sexual function, sexual health differences between men and women?

Kimberley Mak: Yes. We highlighted that when Dr. Westerman was speaking, and we showed the results of your study. Certainly, the available questionnaires are limited specifically for bladder cancer, so it's a matter of finding questionnaires or developing ones that might more specifically address the gender-specific dynamics that are not the same between men and women after bladder cancer treatment.

To that end, as we discussed ARCHER, there is likely going to be—I should say, there are going to be—gender-specific questionnaires that will prospectively collect side effects of bladder cancer treatment in women versus men. That might be, unfortunately, the way we do things is prospectively if there is just not enough data retrospectively to look at this.

Of course, that is our goal moving forward really that any prospective study should have patient-reported outcomes as part of it, and certainly that it seems to be the consensus now in 2024. I think the question is which questionnaire is most appropriate. We're still trying to learn that for bladder cancer sexual domains.

Leslie Ballas: I don't know if the patient mentioned this or in your own experience with your patients, but how common is it for patients to express upfront which quality of life domains are most important to them? Oftentimes, when they're first deciding radical cystectomy versus TMT, they're very much and appropriately focused on cure rates.

How they're going to do from their cancer, but sometimes they don't necessarily think about quality of life upfront, even though that is an important component of their post-definitive treatment life. Did the patient speak about this during the session? Maybe you can again reflect on your own patient population. How do you make sure that you're balancing that discussion with patients?

Kimberley Mak: I think each patient is so different, but oftentimes when they step into your office, they don't know what side effects are going to be a concern. They're still blindsided by this diagnosis of cancer. Of course, as you mentioned, their first inclination is, "How do I be free of this? How do I get rid of this?"

I think it is—the onus is on us as providers to really provide that education on what the differences are between the treatments, obviously both in terms of potential efficacy and also what type of side effects, what timeframe, and the extent of the impairment on quality of life. The patient advocate didn't speak too much about why he in particular advocated more for trimodality therapy.

I think he just knew more about that option than the average patient, for sure. I think he certainly would've been someone to consider each and every side effect and weigh them and determine what's best for him. Sometimes I find that our patients need us to help with that part too, especially in the safety net population that I treat.

The medical literacy rates are just not the same, perhaps, as some of the patients that are advocating for certain treatments beyond what a standard clinician might tell them about. I think it's important for us to be aware of how to frame side effects, how to frame quality of life studies in an objective way as best as we can, to really let the patient drive the treatment decision.

Ultimately, everyone is different, and a choice for Patient A may not be the choice for Patient B. The more we know about general and specific side effects and quality of life considerations in different patient populations, etc., the more we know, the more we can guide our patients. I think ultimately what we want is our patients to feel like they made the right decision with all the information available.

Leslie Ballas: Couldn't agree more. That was really well said, Kim. I think something that some providers struggle with is how to collect quality of life data in the real world, like you were saying. The average age of a bladder cancer patient is somewhere in the 72 to 74-year-old range. Even though electronic collection can help, some patients are less savvy with that.

It's hard to send them the stuff via electronic communication or expect them to fill it out outside of the clinic. When you have a busy clinic and you're trying to get lots of patients through, having them additionally sit and fill out questionnaires, especially if there's more than one questionnaire, can be very time-consuming and provide its own toxicity to the clinic.

I'm wondering if in that section where you guys talked about how to collect this data, if any of those considerations were discussed?

Kimberley Mak: Absolutely. I think that is the biggest issue, actually. We all strive to have every patient with dozens of answers at every time point, and that would generate such a huge database for us to really understand what patients are going through. The reality of the situation is both the patient's time commitment and technology commitment and the clinics'.

We definitely touched on the idea of a burden and fatigue from filling out these questionnaires and discussing what to do for ARCHER. We certainly, in every clinical trial, we have to think about what are the most important symptoms and quality of life considerations to include in our slew of possible questionnaires to include.

We'd love to include them all, right? But it's just not feasible and not realistic even for any patient, even if they had many hours in the day and wanted to, it ultimately gets too burdensome to fill out that many items. I think the questions remain: how can we make it more accessible? Even with someone with limited technological savvy, so to speak, can we engage them in an intuitive way where they could learn quickly?

Obviously, another way is to have a caregiver with them, but that's not always possible, especially in my clinic. Sometimes the caregiver doesn't have that much technological savvy either, so we can't always rely on that. I think that's a struggle with many departments as they try to implement routine patient-reported outcome measurements. Certainly, it's a challenge in our clinic.

That's one of the reasons we're looking at new technology that might be more intuitive than a standard iPad or a computer screen. I mentioned the conversational agent, so that's someone who talks to you, so they're reading essentially the questions, but it's an AI-generated animation, but who looks realistic and might be able to make it a little more interesting for the patient? We're still working on it.

Leslie Ballas: Actually, I think that's one of the strengths of the publication—that your publication—that there were a lot of quality of life domains that were used in those patients comparing radical cystectomy to TMT. I love that paper for that reason because you have so many different questionnaires that you were able to harness.

I think that obviously introducing quality of life and making that a focus for ARCHER and other clinical trials won't have the luxury of having maybe as many domains being used. And so it's a great, at least, baseline for us to have within the field for trimodal therapy.

Kimberley Mak: We included so many questionnaires there because we knew it was a one-time ask, but even, yes, we were worried about how big that packet would be, and I did send multiple reminders and letters just imploring patients who had followed with our clinic at MGH for years. I think they did have some incentive and some desire to sort of give back to the institution, which was so lovely to see.

I think in standard real world, as we talked about a lot of real-world versus clinical trial differences and community versus academic differences as well, we did have to push hard to get the response rate that we did. I think that's just not feasible in normal day-to-day practice. Trying to find that balance of getting enough information, as much information as we can reasonably get without tiring our patients or discouraging them from participating is such a key question here.

I appreciate, yes, the comment that it was a once-in-a-lifetime study there that we were able to pull off, and I'm so appreciative for all the patients that did help contribute to that study, that gave us, as you said, a baseline as to what to work from moving forward.

Leslie Ballas: Last question that I have for you. You started the discussion today with a recap of Dr. Westerman's discussion about salvage cystectomy. We know in modern day that the rate of salvage cystectomy, as you mentioned, is low. If you go with those most recent Slota publication, about 13%, certainly the more modern MGH data would say less than 15%.

What was interesting to me was that she broke it down into also salvage cystectomy for symptoms or toxicity related to TMT. I think that I had heard that the 1806 rate of early sort of rate of salvage cystectomy for toxicity was so incredibly low—single digits. I'm curious about that because I don't know much data about those patients.

You mentioned, how do you determine that? Is it via urodynamic studies? Is it via symptoms? Was there any sort of consensus that was—

Kimberley Mak: This is one of those things that will—we be able to—that'd be amazing, but I think ultimately one patient's threshold for what is too much is so different from the next patient. What is so interesting is that those objective measures might not correspond. We know that from other scenarios in medicine where one patient with the same surgery reports 10 out of 10 pain, the other reports 0 out of 10.

I think ultimately that's why we need patient-reported outcomes because those objective measures aren't enough, and it's really going to be about symptoms. It is certainly interesting that it seems like the quality of life symptoms improved after salvage cystectomy, but of course those are the patients who elected to have salvage cystectomy or were rendered it.

I think you're asking more when does one group move from not needing it to needing it. I think that's that very gray region where it would depend on the patient, the clinicians, and the multidisciplinary team's opinion as well.

Leslie Ballas: We're extremely lucky that that is a very rare thing, that patients actually have toxicity significant enough to warrant a salvage cystectomy for just quality of life purposes. Well, I did just want to say thank you again for having this discussion and for sharing the BCAN Think Tank breakout session. This was really wonderful. Dr. Mak, we thank you, thank you, thank you.

Kimberley Mak: Thanks again for having me. It was a real nice discussion at this session, but also here with you. I loved just recapping and sharing what we discussed because the more people that know about what's going on and think about trimodality therapy, and think about the differences, and how we can find the right patients, the right treatment—that's the most important part of all of this. Thanks again for having me.