Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and I'm joined today by Dr. Hassanzadeh from MD Anderson. Comron, thank you for being here with us today.

We recently concluded the IBCG '25 retreat where one of the topics that we addressed was bladder toxicity and how to measure that in the context of clinical trials. Comron, you led the team that was tasked with a very difficult task on developing a bladder toxicity measurement tool for TMT. And I know that that's a lot of work that's still ongoing, it's not finished yet, but thank you for joining us today, and we'd love to hear your thoughts on bladder toxicity from TMT or radiation therapy in general. So take it away.

Comron Hassanzadeh: Thanks for having me, Ashish. We put together, this was a team effort through the IBCG, along with myself and my colleagues in radiation oncology. There were also urologists on the panel looking at radiation toxicity specifically for patients getting bladder-directed radiation. So this was our consortium guideline opinions that came out of this effort.

So really the question we were trying to answer is how do you adequately assess baseline bladder function when you're trying to decide who is that ideal candidate for bladder preservation, also known as trimodal therapy. We know many men, and women, suffer with issues from potentially their bladder tumor, potentially some of the sequelae from a TURBT prior to radiation therapy, and so assessing that is very key. And that is really important during our consultation as radiation oncologists, but also in consultation and in collaboration with our urologists to identify who maybe doesn't have the best bladder function and who is better served by a cystectomy.

So that's what most of our efforts were leaning to. We know there's not really a formalized way to assess bladder function. We have the IPSS score. We have other maybe quality of life questionnaires, but really trying to nail down what is the most important aspects of urinary function where we're trying to identify those patients who are good candidates for trimodal therapy.

We looked at many data points in a lot of the literature behind this effort. Urodynamic studies have been one way to assess that, and this is a publication out of the Harvard Group actually showing that patients who had better bladder capacity and better urinary flow, and this was predominantly men, tended to do better with trimodal therapy. And so we know this from treating prostate cancer patients. We use the AUA IPSS score, but actually looking at urodynamics is another way to do that, and this idea of sparing a bladder that's worth sparing. Dr. Zietman's words are very, very key and very important.

If you look at the guidelines, so this is the NCCN, EAU, AUA, et cetera, many of them will highlight good bladder function as being one of those key eligibility criteria for trimodal therapy. And so trying to identify who is that good bladder function, whether it's urodynamic studies, et cetera, is very important.

We also shifted gears and looked at how do you actually try to reduce toxicity or reduce side effects during radiation to limit the delays in radiation therapy. So when patients get dysuria, when patients get potentially some urgency frequency that we know is a side effect of radiation therapy, we want to prevent that treatment interruption because there's been data, this is a publication here that has multiple publications that have shown a delay in treatment with bladder radiation has actually led to worse outcomes. And here's another cohort from the VA with similar data showing a discontinuation of radiation actually led to worse outcomes than those that did not have interruptions in the therapy.

When you look at technology of radiation, we're in the IMRT era for bladder radiation. If you look at the older studies, especially the seminal BC2001 study, many of these studies were done with 3D conformal radiation. And you can see that represented here as a very simple APPA and lateral field that ended up treating a lot of the nearby structures, such as the bowel, the rectum, et cetera.

Now in today's era, we're using a lot of IMRT, intensity-modulated radiation. But in this era, how do we optimize, how do we use this technology in the best way possible? How do we make sure patients are lining up in the appropriate position in order to further reduce their bowel and urinary side effects?

These are several publications that we looked at in our group that showed ultimately IMRT has been shown in many other disease sites, but especially in bladder cancer, to reduce GI side effects. And then also there's been publications showing potentially even a reduction in GU or urinary side effects as well.

And then this idea of how do you take that IMRT and make sure that you're not missing a bladder that is actively trying to fill during radiation therapy? And these images are important to know because we might have a patient who's coming in with a full bladder, but a full bladder can mean many things for certain patients, and we want this to be a reproducible setup on a daily basis outside of adaptive radiation. Our tried and true radiation has a margin that we build in for this treatment, and so trying to make sure that we're accounting for bladder filling during treatment is really important.

There have been several studies. These are older publications, but we looked at these studies to help guide us on what is the best way to account for this motion of the bladder and make sure that we are accounting for that being accurate in our treatment, making sure we don't have a geographic miss during radiation. And you can see these are just representative images of the bladder actually filling in more of a superior anterior direction and how we might need to account for that during radiation treatment.

Lastly, I think when you're talking about trimodal therapy, you need to conceptualize what is the side effect profile, both acutely and in the late phase. We know many patients will have side effects during their later course, later parts of their treatment. So that's week four, five and six, depending on whether they're getting 20 or 32 fractions or hypofractionated or conventional fractionation.

And so I think being upfront with your patients and leaning on the data to say, this is your risk of GI side effects. This is your risk of urinary toxicity. We know things like gemcitabine, concurrent with radiation, have a little bit higher GI profile. And so these are things to really, I think, review with your patients and make sure there's informed decision making.

And then things like patient-reported outcomes as well. We know that your quality of life does take a hit during this acute phase of radiation, but just being mindful that this recovers with time, and that these urinary side effects, these bowel side effects will recover within weeks after radiation for the majority of patients.

And then after treatment, what comes next? I think we wanted to make sure that while there are guidelines, you can see the guidelines from ESMO, EAU, AUA, et cetera, on how frequently you need to do cystoscopies and CTs after trimodal therapy. This is definitely an area that we need further research, but we try to make some statements on this to help guide physicians and radiation oncologists and our friendly urologists who we refer to get these cystoscopies on a regular basis.

And so I think these are the main takeaways from the study are that when you're looking at bladder-directed radiation therapy, this quality of life, and I think having patients fully on board, making them aware of the whole side effect profile, making them aware of who is a good candidate, who is not a good candidate, how to assess bladder function, and then lastly, being able to assess that quality of life spectrum is very, very key.
So with that, Ashish, I'll let you take over.

Ashish Kamat: So thanks, Comron, for presenting the data that you presented at the retreat. Now one of the charges that we had for you and your group, which I know is a little bit challenging, is to develop a bladder toxicity measurement schedule or tool for patients that are undergoing radiation therapy, or TMT, as part of a clinical trial because it's very important for us to figure out what is the impact on quality of life. How does it affect, say, if you compare that with those getting intravesical therapy, as is in certain cooperative group studies right now or in patients that are undergoing radical cystectomy?

So without getting into too much detail, because obviously that's still a work in progress, share with us some of the discussion points that were brought up during your session.

Comron Hassanzadeh: So I think when you're talking about this idea of bladder preservation, which I think nowadays takes on a new meaning, it used to be trimodal therapy was bladder preservation, but now there's other forms. For muscle invasive disease, you're seeing a lot of innovative trials coming out looking at doing systemic therapy and watching patients. And so I think this idea of bladder preservation is an evolving field.

Specific to radiation, we wanted to make sure that quality of life and patient-reported outcomes are built into many protocols going forward. We know physician-reported toxicity many times I think undercounts a lot of the real toxicity from radiation. So really hearing from the patient and keeping it very... I think keeping the patient advocates and their voices heard on the studies through patient-reported outcomes was one thing that came across in the group.

In addition to that, I think trying to look at this idea of bladder function and assessing bladder function as a maybe eligibility criteria for enrollment on some of the clinical trials was also something that did come up in the group and trying to find a way to do that in a maybe reproducible manner across different studies.

And so these are, I think, probably two of the main points that came across.

Ashish Kamat: I think what was really eye-opening for all of us was hearing from the patients when they talked about grading of toxicity because when we consider, say, grade 1, 2, 3, we tend to discount grade one or grade two toxicities, for the most part, when we are looking at clinical trials and drugs or devices. But hearing from the patient, well, if it's a grade one that's happening every day, for me, that's a huge burden, and sometimes you have to factor that into surgery, treatments, intravesical radiation, et cetera. Have you started factoring any of these newer patient-reported outcome tools into your actual clinical practice?

Comron Hassanzadeh: Yeah, so I know we've incorporated some of the EORTC MIBC patient-reported outcome modules into a lot of the investigator-initiated trials that we're looking at. I think these are probably going to be better incorporated as well on many of the cooperative group studies. Both at SWOG and NRG in the United States I think are incorporating more patient reported outcomes.

So I think we've come a long way from just CTCAE, to your point, which I think was really I think eye-opening point that some of the patient advocates brought up was grade one is not so severe, but if it's a grade one toxicity that becomes permanent, well, that may actually be more relevant to me than a transient grade two. So I think these ideas of building in patient-reported outcomes very intentionally into protocols is I think being heard and is being incorporated.

Ashish Kamat: Great. Always a pleasure having you at the retreat, Comron, and really looking forward to seeing what the group comes up with as a finished work product. I'm sure we'll have another session with you here on UroToday to talk about all the work that you're doing with the IBCG, so thanks again.

Comron Hassanzadeh: Thanks, Ashish.