Camron Tharp's TAP Journal Club: The Bart Trial

TAP kicks off a journal club format by dissecting the phase III BART trial on adjuvant radiation therapy after radical cystectomy for muscle-invasive bladder cancer. 

Cam Tharp, MS hosts radiation oncologists Drs. Comron Hassanzadeh and Stephanie Dudzinski to led discussion of this important trial. 

The Accelerators Podcast is a Photon Media production. For more from Matt, visit his website. For more from Simul, visit his blog, Radiation Medicine: Dollars and Sense.

Transcript

SPEAKER_03 0:16

And they represent our own opinions and not those of our employees. Thanks for being here.

SPEAKER_01 0:21

Let's get on with the show. Thanks everyone for joining today. My name is Cameron Park. You call me Cam. Some people may know me, some people may not know me. I am a part of the Accelerators podcast, but I mostly just participate from behind the scenes. And uh but today we're doing a little something different. We wanted to start a new project. I've been kind of talking about a journal club for um quite a while. I'm a uh PhD student in epidemiology at our uh School of Public Health uh at UT here in Houston. And so a lot of my a lot of my uh activities uh in class uh have revolved around like journal club discussions and and those kinds of activities. Um and I thought they were so useful for learning and uh and and for just bringing together people and talking about something that we're all interested in. And um, you know, everyone everyone can learn something um from this and and participate in it. It's it's just kind of nice to um so thanks everyone who's joined uh so far. Um let's get started. Uh like I said, my name is uh is Cam. Um, but we do have some special guests uh here that hail from my neck of the woods in Houston. Um uh Dr. Hasenzada, Dr. Dudzinski. Um, you can feel free to introduce yourselves.

SPEAKER_00 1:49

Hey, uh I'm Tamar Hassanzada. I'm an assistant professor in radiation oncology at MD Anderson, uh focusing on genital urinary cancers. Happy to be here. And thanks, Cam.

SPEAKER_04 2:00

Hey y'all, I'm Stephanie Nadzinski. I'm a PGY5 resident physician at MD Anderson. Um, and I will actually be joining the genital urinary radiation oncology department here at MD Anderson. So a lot of this bladder cancer treatment is my future, hence why I'm very thankful and excited that Cam invited me to be part of this podcast. So thanks for the invite, Cam.

What The BART Trial Tests

Standard Care And Why Recurrence Hurts

SPEAKER_01 2:23

Yeah, of course. And um uh let me give you a formal congratulations. Um, I didn't know if anything was like announced yet or not, but um definitely congratulations. I'm excited to be emailing you um about bladder volumes and uh and whatnot. Um so, like I said today, we're gonna be talking about the BART trial. For those who don't know, uh BART stands for bladder adjuvant radiation therapy. Um, this is a nice, very nice uh phase three superiority RCT uh multi-center uh study uh out of India, I believe. Um and we decided to do this study first, um, primarily because of something that I don't really know about. I'm a radiation therapist at our Proton Therapy Center here, and so we don't really see a lot of bladder cancer treatment um at a proton center. Um and so I am kind of using this selfishly as an opportunity to learn about something that I don't know. Um but also I did I did really enjoy reading this study um and and dissecting it a little bit, and I'm excited to have some experts here to talk about uh all these findings and methodologies. So um we're gonna come back to this study design for um the remainder of this uh this presentation. Um so it's a pretty classical what I when I think of of an RCT, I think it's a pretty classical example of what a randomized control trial is. It is a phase three superiority trial. Um for those of you who may be new to clinical research, uh, phase three trials are kind of the gold standard of clinical research outside of meta-analyses. They usually have a larger sample size than phase one or two trials, and they usually primarily want to test uh an effectiveness of an intervention, uh, a new intervention versus the standard of care therapy or or placebo. Usually they also uh are required to have toxicity monitoring as a part of this uh secondary and uh uh endpoint. And they also require a pre-specified uh predicted effect size, which is the difference in the effect of the primary endpoint uh between the intervention, the new intervention, and then the control group or placebo. Uh so they'll be able to use this effect size to calculate the appropriate sample size, um, and it'll account for power, usually 80% or higher, and uh and account for attrition. So this study um they had uh a predicted effect size of 15%. We'll get into this a little later. Um first let's let's just get started talking about the history of radiation therapy uh for bladder cancer and for some uh to set some context. It says here that standard of care for muscle-invasive bladder cancer is neoadjuvant uh chemotherapy followed by radical cystectomy, plus or minus prostatectomy with bilateral pelvic nodal dissection. Uh, could either one of you kind of comment on this? Is this kind of appropriate care that we would we would uh see here in the the United States?

SPEAKER_00 5:54

Yeah, so um I think in general for muscle invasive bladder cancer, so you know, that's about a third of all bladder cancers diagnosed in the United States. So it's actually relatively rare in general. So most, you know, if you have uh anybody that you know with bladder cancer, majority of those patients actually have non-muscle invasive, which is not really what we're going to be talking about today, but for muscle invasive, right? About a third of patients who are diagnosed with bladder cancer have uh urethalial, typically cancer invading to the muscular layer of the bladder. Um, those patients have two options uh for kind of the modern day literature. And I think you cited it really nice in Cam. Um, one is neoadjuvant therapy, uh it could be chemo, but nowadays we're doing a lot of other things, followed by cystectomy, and that's many times with pelvic lymph dissection or bladder preservation therapy, and that is with chemo radiation, um, usually followed by um you know some type of adjuvant therapies. But um, those are really your two options. Uh Steph, I don't know if you want to add to that at all, but nothing particular to add.

SPEAKER_04 7:00

Just wanted to also say that, you know, recently some of the guidelines have been updated to highlight those two as an option with surgery or kind of trimodality therapy as being an option for patients. Um, but historically, a standard of care and and often still is pneoadjmic chemotherapy followed by therbatosystectomy. And I see that you have prostatectomy with a question mark listed in here. Our our male GU patients will have a prostatectomy with that. And obviously, our female patients will will not have that part of the surgery.

Why Modern IMRT Changes Toxicity

SPEAKER_01 7:33

Gotcha. Yeah, thanks for that context. I thought it was it was pretty interesting. Um, I guess maybe it owing to the anatomy of where the the posse is uh relative to the bladder. Um I just thought that was very interesting. Um I'd never heard of that before. But obviously, prognosis is pretty poor with these patients um with muscle-invasive bladder cancer that I was reading. Again, I don't know much per se professionally, but I was reading that uh after cysteomy alone, uh five-year uh overall survival can range from 10 to 40 percent with an additional absolute uh benefit of 5% with the additional chemotherapy, either neo-adjuvantly or adjuvantly, um, which can range uh by you know pretty it's a pretty poor range, I I I feel. And so local regional control may be important. Um so they cited that there was 30 to 50 percent local regional control uh with surgery alone, and that public recurrences for MIBC are common and very hard to salvage. There should be an extra focus of local regional control um leading to less recurrence, less uh distant net, and possibly increased survival. I wanted to talk about historical radiation with uh with uh relation to bladder cancer. It seems that they they cited a couple of old studies um in the 90s or earlier that radiation has good control for bladder cancer within the pelvis, um, but the toxicity can be pretty poor.

SPEAKER_04 9:14

I I I might jump in and then have you give the more polished comments or experienced comments afterwards, Dr. H. So, you know, in general, when we think about the history of radiation and when you're talking back to the 90s, etc., a lot of our treatment planning looked drastically different. We were back in a 2D era or a 3D era, you know, IMRT started becoming more popular in the 90s, 2000s. So when you're giving radiation treatment that isn't as targeted, right, you can't avoid some of the organs at risk or the things that we're trying to limit our dose to as well. So, from that context, right, when we're thinking about the toxicity, our treatment plans now, we can create these beautiful IMRT or VMAP plans. Some trials even have a plan of the day where you're doing, you know, cone beam CT imaging and giving the plan that best fits how the bowel looks that day. So we're able to provide much more targeted doses to that cysteomy bed and the adjuvant setting and/or lymph nodes. We can talk, I don't know if we'll talk about that later, um, but try to avoid or minimize that dose to the bowel since it is often a frequently moving organ that we can now adjust better for with new techniques and new IgRT. So I think a lot of it is a technology improvement of why historically we had a lot of bad toxicity and that we couldn't avoid some of the organs at risk due to lack of IGRT and not as advanced radiation techniques. Dr. Hasanzada, any other comments?

SPEAKER_00 10:54

Yeah, those well-put stuff. I think um, in general, um, you know, specific to the study we're going to be talking about today, uh, when you get when patients are undergoing cystectomy, many times there's risk factors, and we'll talk about those that put patients at pretty high risk for local regional recurrence. And those patients specifically, like uh you know, large tumors, known positive, positive margins, these are all indications and other disease sites, right, that we consider adjuvant radiation and for bladder. Um, that data is limited, although the study we're going to be talking about today really added to that body of literature. But I think to Steph's point, although we're not going to be focusing on bladder preservation that much for kind of like post-systectomy for the most part, um, I think trimodal therapy has become in many ways a uh, you know, a great alternative for many patients who are candidates to preserve their bladder. But for those that have had a cystectomy, I think local regional recurrences, uh, you said it very well can, are very morbid for patients. So avoiding that, while it may not translate to improvement in survival, may actually translate to a better quality of life and allow patients in in some regards to potentially improve their oncologic outcomes.

SPEAKER_02 12:06

I had one thing I wanted to ask really quick. So, like I like I the conversation you had just to kind of the other side of it is kind of the historical radiation bad, right? So, like I actually talk a lot with my patients, regardless of the disease site I'm treating, if it's pelvis, that we actually have prospective data that shows improvement in quality of life with IMRT compared to 3D from the Gyne world. Is there anything like that in GU or in bladder? Because I not that we need it. I think you can translate it across to men or or women with bladder cancer without like it's not like there's a special thing about female pelvis that makes it relevant. I just I guess my question is, is there like direct data that we could apply there? Because you can tell your colleagues that are outside of our field that we actually can show prospectively that the better technique makes people do better. It's not that common that you can show that. And I think it's a really powerful piece of data.

SPEAKER_00 13:01

Yeah, uh I think that's a great point that you bring up. Um IMRT, and we know for for GYN, it probably actually, I guess, caught the ball rolling in many ways for pelvic malignancies to start incorporating more IMRT, less 3D. Um, and you're right, historically, pelvic radiation, you know, we hear the stories of the patients who were treated back in the 90s, early 90s before IMRT was very popular. And they they tell you stories of significant, you know, bowel toxicity, bladder toxicity, because that was potentially the norm when you receive 3D conformal radiation. And a lot of that has now been reduced, not eliminated, but reduced with IMRT. Uh to GU specifically, we have a lot of data for prostate. Obviously, it's the standard of care for IMRT for prostate patients to get IMRT. For bladder, there's less. Um, there is actually, you know, I've been asked this question a few times and having to support patients getting IMRT. Sometimes insurance companies will bounce back and actually want you to provide that data. And there's a few retrospective series that have compared an older cohort of 3D versus a newer cohort of IMRT and compared bile toxicity and shown a significant improvement in bile toxicity. And that you know mirrors a lot of the data in GYM. Uh, you know, I don't know if Dr. Delzisti wants to add to that as well.

SPEAKER_04 14:20

Um, I don't have anything to add in particular. The the study you're referencing was the that time C trial by Dr. Klopp here at MD Anderson. Um, you know, I think I think something that's important as we talk about different pelvic sites from one to another, right, is a little bit of like right with prostate cancer, we are having patients often have a full bladder to try to reduce dose to bowel. So I think in these different settings where for females, if they've undergone hysterectomies, or in this setting, right, patients that have undergone cystectomies, you know, the bowel is going to look different and be able to move different. So I do think that's interesting if we have data. I'm not aware of any, like Dr. Hasenzada said, but I think I don't think necessarily a pelvis is a pelvis. I think you have to think about what the disease was and what organs are in there that may help mitigate or decrease some of that dose to the bowel.

High Risk Features And Patient Selection

SPEAKER_01 15:13

Gotcha. Yeah, thanks for all that context. This is like great food for my brain right now. Um I did, I was thinking whenever I was putting this presentation together that um they mentioned like a lot of high-risk factors or high-risk parameters that um or features, excuse me, that these patients have um with muscle invasive bladder cancer. And I know that uh for certain sites that there's risk stratification, like in prostate, there's um high risk, low risk, favorable, intermediate, what etc. Um, is there this stratification in bladder cancer? And if there is, do you um in the in the case of like this rare higher higher risk bladder cancer cohort or population, do you extrapolate your management from lower risk, like more common bladder cancers into this higher risk cohort?

SPEAKER_04 16:05

So there was data from Dr. Baumann's studies at Penn with bladder cancer and looking at kind of risk stratification in this adjunct context, right? A lot of the high-risk aspects that were included in this trial, the PT3, T4, positive margins, less than 10 lymph nodes dissected, were some of the ones included. And then the additional one were patients that had clinical T3, T4 that got neoadgent chemotherapy. From his work, he also had a low-risk group that was P, T0, T2, that for that category at five-year had a local regional recurrence rate of 8%, and then their high-risk group, I think, had a local regional recurrence rate of about 40%. So clear discrepancies between their high-risk and low-risk group. Um, that is at least how I still think about and stratify some of those cohorts, and that's some of the rationale of how uh Dr. Murphy, I believe, designed this trial. Um, Dr. Hasenzot, I know you've taught me this before. What other what other comments would you like to talk about?

SPEAKER_00 17:09

Uh I I guess the only thing I would add is you're exactly right. Not all patients need adjuvant radiation after cystectomies. Um, actually, the majority don't, because we we are pretty good at um, you know, with that neo-adjuvant systemic therapy that you mentioned, can many times we're getting patients to pretty good respectable status so that their cystectomy is actually fairly effective. Now, there's a population that has larger tumors, no positive, where it actually may have a benefit. And the inclusion criterion Barbara will talk about uh really captures that population. So I think big picture, if you've had a cysteomy, you know, the modern day standard of care is to get adjuvant uh immunotherapy. Usually it's an Ebola map uh per some of the you know initial uh immunotherapy studies that were run a few years ago. But there is a population that maybe we combine radiation in addition to that maintenance idio part of datotherapy.

Eligibility Rules And India Versus US

SPEAKER_01 18:09

Gotcha. Yeah, I um so the Red Journal uh podcast actually covered, I believe I think it was the Red Journal podcast actually covered this trial. And um one of the bigger limitations that they that they talked about was the lack of uh immunotherapy uh availability um for this trial. Um and so that's that's something considerable to look at in the future. Um so eligibility uh in this this study um was pretty intense, I thought. Uh it was a pretty uh selective for sample. Um they had to have urethelial carcinoma. Um there was urethelial carcinoma plus um a percentage of those who had like a variant histology as well as the urethelial carcinoma. Um they had to have radical cyssectomy, one or more high-risk features, which include uh nodal involvement plus perinodal extension, positive margins, p3 and T4 status, uh, and then less than 10 nodes dissected. Um they also had to have either neoadjuvant chemo or uh adjuvant chemotherapy. They had to have a performance status of greater than 70 and then adequate blood counts and uh liver and kidney function. Uh in some exclusions, they had to not have um discent Mets or periotic METs or private or uh excuse me, prior pelvic XRT. Uh they couldn't have any contraindications to XRT, of course, or uncontrolled comorbid disease. And uh if their follow-up wasn't possible, then they were excluded. Um I wanted to talk about the patient sample here in this trial and some differences that I that there may be in a US sample. Uh it says that their median age in in this population was 57, which I don't know, I don't know if I'm correct. I think that's like quite a bit younger than the the average bladder cancer patient that we see. Is that correct?

SPEAKER_00 20:27

Yeah, so um there's some really good things to highlight in the inclusion criteria in this table one. So uh exactly, younger patients were enrolled on this study. This is a Tata Memorial Indian study, right? So a different cohort of patients that we may see in the United States. So younger patients, um most of the diagnoses of bladder cancer in India. This is speaking with some urology colleagues who are very familiar with this, is due to um some toxins uh that a lot of patients get exposed to. And um, it's kind of like a chewing tobacco, uh, and it has actually a carcinogen in it that leads to high rates of bladder cancer, especially in men. Uh, so it's not so much smoking, right, which is the main risk factor that we know in the United States. It's actually a specific carcinogen that we don't see in our US population. And that probably leads to younger men predominantly being diagnosed. You can see obviously 89% are male, about maybe 10, 11% are female. That breakdown is maybe not so unexpected. We see maybe uh a three to one or even four to one male to female ratio in the United States. But I think the age is a big difference, right? The median age of water kids in the United States is about 70, 75. So you're already seeing about a 20 year difference. And I think in many ways, that already is a different population. The one other thing I do want to highlight is you didn't mention this, Cam. Uh uh, I think it's worth maybe reiterating. Urethelial carcinoma is kind of your classic type of histology that's Enrolled. There's a small cohort of patients on this study that were variant. This differs from the older studies that were done in this space of adjuvant radiation. And those are mostly done in the Egyptian core, with Zagul et al. being the primary author. Those patients are predominantly squamous cell. And that population definitely does not extrapolate to the United States, where we do not see high rates of squamous cell bladder cancer. We may see a small component of squamous cell, but we predominantly see urethalial carcinoma. And the reason that Egyptian population has squamous cell is due to the endemic schistosomiasis that comes from the dialogue of Delta. And we don't see that in the United States very commonly. So I think this cohort, while younger, it is actually histologically more of a comparison, a better comparison to the United States.

Randomization Details And Crossover Reality

SPEAKER_01 22:54

Yeah, that's a great point. Because whenever we like whenever I'm thinking about, whenever I'm reading a study, thinking about quality of life performance, um, like how well they do after therapy, like age is like something that I think about pretty heavily. And and I guess like it doesn't to me, like it doesn't really um even register like where where the study was done. Um I just I feel like uh patients who are younger are like going to do better, probably no matter where they where they are, just performance status-wise. Um but it it's a great observation to make in in the comparison of of like the Egyptian cohort uh with the squamous cell. Um I had not read that, and that is really interesting to me. Um and so it it's it's good to know that that this cohort may be actually pretty um, like you may be pretty like well able to extrapolate data from this this cohort, or it may be useful to your clinical practice. Um I did also notice that the body max body mass index median was 22.6, which I think is like quite a bit lower than our median here in the United States. That's like low-hanging fruit, um, I'm sure, but and I don't really know if it's clinically relevant or not. Um but in table one, we see that the cohort or the groups are pretty well balanced. Um, that randomization did really well. And to just speak about randomization a little bit uh more, they had a one-to-one randomization. Like I said, this is a pretty classic example of a randomized control trial, in my opinion, uh head-to-head one-to-one randomization between two different uh interventions or controls. Um they utilize stratified block randomization, uh, which is a really helpful tool to both uh ensure that not only the characteristics of the patients are well distributed between the two groups, but also that the number of patients are uh well distributed between the groups. Um the utilized um uh stratification between pathological node status and uh chemotherapy, either neoadjuvant or adjuvant or none. Um and then they also uh used the the block randomization, though I didn't find um any comments on what their block size was, though I don't think that really matters all too much. Um randomization was well done uh between the groups. They ended up with the uh I believe they it um they questioned or they looked at about 250 patients. Um after exclusion criteria um and an eligibility criteria, they got down uh to about 153, 153 patients, randomized them one-to-one. Uh 77 were allocated to radiation, 76 were allocated to observation. What I thought was really interesting is that there was a component where a bit of crossover happened. Um, if they were randomized either to radiation or observation, it see it seems here that um six patients refuse uh radiation therapy and were allowed to cross over to the observation arm. Um have you ever encountered this in your practice, or is this kind of like a typical thing that happens sometimes?

SPEAKER_00 26:36

Um so yes, I think it happens quite frequently. Um, you know, randomizing to basically observation versus radiation is challenging because usually uh you'll get biased both ways. Some patients are very reticent to undergo radiation treatment, and then they are randomized to that arm and subsequently may want to withdraw from the study. So we see that commonly. There's also the flip, right? Some patients may be very enthusiastic about treatment, don't get randomized to radiation, and actually will like to proceed with radiation off study. So I can see it actually going both ways based on much of the fallout in the study. It actually seemed to be the former issue that most patients were somewhat hesitant to undergo radiation and were randomized to that arm and subsequently did not want to proceed.

SPEAKER_04 27:25

Yeah.

SPEAKER_00 27:25

Right.

SPEAKER_04 27:26

And in some trials, in thinking about design and the risk of that happening, and we haven't, we've only seen toxicity data for this study. We haven't seen the outcomes yet, right? But you can then think about, you know, kind of treatment per protocol or what they were randomly assigned to versus, or sorry, what the intention to treat was versus what treatment they actually received. Um so sometimes when people are designing and have that concern, sometimes they'll look at both like Dr. Frank's recent proton versus photon head and neck trial, they analyze both the intention to treat and what they actually receive for treatment as like separate analyses due to that concern.

Dose Choice And Planning Constraints

SPEAKER_01 28:06

Yeah, those that's that's great information. And um I know like usually with when I think of a superiority randomized control trial, I think of intention to treat really. Um, and that ideally the intention to treat and the per protocol don't differ much if attrition is low. Um and I don't think attrition was very high at all in this uh in this study. And I wanted to ask about the radiation dose. Um, did you two think that this dose was appropriate? Uh like I said, I'm unfamiliar with bladder cancer. Um, they treated to 50.4 gray to the cystectomy bed and the pelvic lymph nodes uh in 28 fractions. Uh, if they were R0 and if they did not have an R0 resection, it looks like they slightly dose-escalated to 54 to 56 gray uh with the same 28 fractions. Is this a dose that you think is is pretty standard, or is there uh a chance to dose escalate, or um maybe is is it worthwhile to think of dose-escalating?

SPEAKER_00 29:15

So I think in general, um, you know, 50.4 gray, 28 fractions, uh, yeah, 1.8 grade per fraction is pretty standard. Actually, that's what um you know most of us do in this setting. Uh some of the older Zagul data, the Egyptian studies did two gray per fraction, and there was actually one that looked at VID fractionation. Uh so you can do 50 gray and 25 fractions, two gray per fraction, or do 50.4 and 28. Uh, in general, you're seeing these doses being relatively low, right? Um, there's one reason for that. It's because there's no longer a bladder. All the bowel falls into the pelvis, and we know about how sensitive the bowel is to radiation. So, as much as you want to maybe deliver a higher dose, especially for patients that maybe have gross disease, residual disease, or high risk for local recurrence for like positive margins, you really can't do it safely. Um, and also uh we're gonna be taking a look at the volumes in a second. The volumes are very generous. The cystectomy bed, very generous. Um, and also the pelvic nodes, we we know that can lead to bowel toxicity as well. So you really just have to go slow and easy. You can't do anything significantly hypofractionated in this setting. We're all 1.8 to 2 grade per fraction.

SPEAKER_01 30:31

Would you consider like sparing dose to the rectum in these cases like pretty difficult? Or what is your what is your main goal of uh of your your dose constraints when treating like patients like these?

SPEAKER_00 30:47

Um yeah, I guess uh there's a few things to take away. Uh, I really do like that they gave a lot of information about how they plan these patients. Um and Dr. Dunstee highlight and Dr. Bauman has a very good contouring atlas for cystectomy betin. Um, and that actually is in many ways our best contouring atlas we have today. You have uh nice kind of screenshots of that uh representative samples. So um one thing to take away is that yes, bowel falls right into the field. It's very hard to spare the rectum. In general, you know, if you think about how we treat rectal cancer, um, we know the rectum can tolerate doses that are 50 gray or less. You are gonna run into issues with likely some mild nausea and some maybe grade one, grade two, and in some cases grade three diarrhea that you need to get ahead of and be very proactive about. Um, the other thing that is very important is many of these patients are gonna have an ilioconduit. Um, and that urostomy and ilioconduit is a very unique factor, right? They don't have the bladder. You've taken a piece of their ilium or bowel, connected it to the ureter, and now that is the way that they're able to, you know, basically have a way to get rid of all the urine without having a bladder. But that is really not bladder, right? That's actually bowel tissue that we're using as a conduit. So the last thing you want to do is overdose or not be mindful of that ileal conduit and lead to a stricture or complication. And I will tell you my urologists uh really worry about that and bring it up quite frequently is that are you going to cause a problem for my conduit? Because a revision surgery is very, very complicated for that type of scenario. So they actually nicely highlight how to contour the ilioconduit and how to avoid it, uh, almost treating it like we treat some type of implanted devices in patients, right? Like if you think about a pacemaker, we put set very hard constraints on something like a pacemaker, and in many ways the conduit is treated similar to that.

SPEAKER_01 32:49

Um I wanted to talk to you about these endpoints. Um, when we're talking about radiation therapy, um, my mind goes to uh disease-free survival and local regional failure, progression-free survival, et cetera. Um are these are these um endpoints that they use, like a local regional failure-free survival, I think it's pretty appropriate. Um, and then there I've heard like some discussion about around other other trials that overall survival maybe should not be a great primary endpoint for a radiotherapy trial. Um, could one of you comment on that?

SPEAKER_04 33:26

I'll take a I'll take a stab at it first. So, you know, when you say that other trials are considering other endpoints, I think the really important thing to think about when we're looking at different disease sites or different trials is number one, like what's going to happen for this patient if there is a local recurrence? Is there going to be a lot of morbidity? Is there a salvage option, right? But also with respect to this patient population, like what's ultimately is there demise if there is a cancer-related death for this patient? Right. So I think for this setting, Dr. Hasenzada already kind of commented on the morbidity that can happen if you have a local recurrence after cystectomy. So for that reason, I think the local recurrence free survival, disease-free survival, and overall survival are important. Whereas if there are other disease sites where you can like have a recurrence, but there's a good salvage option, then maybe the overall survival isn't as important for that aspect. Um, but it's when you have a good salvage option available. So that's how I think a little bit about these outcomes is what happens for that patient if there's a recurrence. Is there a salvage option? And if a recurrence happens, like what kind of toxicities can happen for that patient and how can that impact their ultimate survival? Dr. Hasenzada, what how do you think about these?

SPEAKER_00 35:00

Yeah, I think you're right on. I agree. Um, most of these studies looking at adjuvant radiation. And I think it's it's actually the case in many different disease sites. We don't expect to impact overall survival many times. We're really trying to address local regional recurrence. Now, as a radiation oncologist of my own bias, I hope it translates into improving DFS and OS, but it rarely does. Usually it's the medical oncologist that makes that difference for bladder cancer patients, right? With systemic therapy advances, we've moved on from chemo in the adjuvant setting, or in patients who develop recurrent disease, and now we're wondering about what your salvage systemic therapy looks like. And in many patients nowadays, that's either immunotherapy or with the advent of antibody drug conjugates, we're using a lot of uh EV, important Vidotin, or similar antibody drug conjugates, which are really the next level of systemic therapy for bladder cancer. And we didn't talk about it that much. Um, but systemic therapy itself, um, regardless of our advances in radiation, has already improved outcomes for muscle-invasive bladder cancer pretty significantly, actually, within the past five years, um, to the point that at the past few ASCO and ESMO conferences, every time they present a new bladder cancer systemic therapy study, it gets a kind of like an applause, right? Like everybody gets on their feet and it's an applause because you notice the overall survival compared to you know our historical five-year outcomes has forwarding made leaps and bounds improvements. So I think you're right, Cam. I think you're right, Dr. Delsinski, that local regional recurrence free survival is really about as good as it's going to get for us. Um, whether that translates into overall survival, who knows? I think maybe with better systemic therapy advances, we control the distant occult with Mets, and then potentially we address the gross residual disease. And potentially that translates into better alcoholic outcomes. But we we don't really dump that for sure.

Toxicity Results And Clinical Confidence

SPEAKER_01 37:03

Right. That's that's great data. It's um yeah, I I like the the picture of the the standing ovation. I can imagine, I can imagine how that is. And um and it's kind of frustrating um to read uh these or or really to listen to like other other podcasts about uh medical oncology um advances and um and and relating back to radiation therapy, but I think our field is getting so creative, like with Dr. Dudzinski um mentioning about like the plan of the day thing. That is something that I did not know was happening, um, which I think it is super interesting. Um But yeah, I think local regional uh failure is something to consider with these um with these patients. Um like I said, I I don't know much about bladder cancer, but um knowing that pelvic recurrences are hard to manage, um I think giving these patients who are eligible or would potentially benefit from adjuvant radiation, um, giving them their best chance for uh recurrence-free survival is is so important. Um moving on to toxicity, I think one of the biggest takeaways I had from this study is how well patients handled this therapy, um, which historically had not necessarily been the case. Um let me zoom in here. You can see um these incidence curves here um do really well. Like I I expect um I expected reading this trial with um for these patients with bladder cancer with pretty large fields of of you know the cystectomy bed and pelvic nodes, um, I I feel like I suspected some pretty um substantial incidence of high grade toxicity, um, which didn't necessarily happen between the two groups, observation and and RT. Um I believe that uh let's see. I don't have our estimates here, which I probably should have put, um, but I think they're pretty comparable. Um, and I don't know if they were significant or not. Um, but knowing that this, that this therapy was well tolerated in this cohort, um, does this give you as a the clinician extra motivation or confidence of being, you know, I guess aggressive with these patients with high grade disease, not necessarily aggressive with dose, but um maybe giving you more confidence that radiation is actually more uh tolerable than previously stated.

SPEAKER_04 40:04

You know, I think you know, we talked about the dose and we've talked about dose constraints, right? So with the dose that we're giving, right, we're not doing a lot of crazy dose escalation that's outside tolerance for some of these organs. Um, like 50.4 and 28 and and other fractions, right, have been 50 and 25 and 1.8 is quite gentle. So for that, I would say that I wasn't too surprised by the toxicity rate for these patients for the acute toxicities and that they tolerated the treatment well. Um you know, I think anytime when a patient comes after surgery, and at least anytime I see patients for the the we highlighted the importance of like the ilioconduit, or anytime there's a new anastomosis, that's the area I worry about the most. Um, but like Dr. Hostensada said, is we plan very carefully to make sure not to uh irritate that tissue too much or cause too much damage. And so from an assessment of the rectum, the rest of the bowel bag with the large and small bowel, like these are doses that I would expect it to tolerate quite well. Um, so these toxicity rates did not surprise me. What about you, Dr. Hasan's Ada?

SPEAKER_00 41:22

Yeah, I agree. I think um the toxicity here is very well tolerated. In fact, um it's much better than the older kind of Egyptian series that we read about. And I think there's a few reasons for that. They set pretty nice uh bow constraints. They used IMRT, 3D conformal. So that itself, I think, already made a huge improvement. Um, is just switching to IMRT and then um being really mindful of the fact that maybe we do need to go in 1.8 instead of two grid per fraction. And then the old Zagul data of doing VID fractionation actually led to a fair bit of toxicity. So that has fallen out of favor as well.

SPEAKER_01 42:01

Right. And so I have the um off-screen, I just have the the estimates um pulled up. So two-year local regional failure-free survival was 87.1% versus 76% in the observation arm, which was pretty uh substantial and pretty accurate with their uh effect size um prediction. Um, that led to a reduction in in hazard of 57%. So the hazard ratio was um 0.43, yeah, which was significant with the p-value of 0.04. Um obviously, like we said before, this data is probably premature to uh talk about overall survival, which they um did not see a significant difference in. Um they also mentioned quite eloquently that there was no isolated um local regional recurrence with radiation therapy, which I think really translates or or speaks well to the effectiveness of radiation therapy. Um when they mean isolated local regional uh recurrence, um, could you give the audience kind of what that means?

SPEAKER_00 43:17

Yeah, so I I think there's a few points there uh to just echo. Um, you know, when we're talking about local regional recurrence, that means a recurrence in the cystectomy bed, really. Um, but could also mean recurrence within some of the pelvic nodal fields. So it's really the irradiated field. Um, and you're right, there was no isolated recurrence. I mean, there was no patients that just had a recurrence in the cystectomy bed or nodal fields as their only site, which tells you there was a small population that did have cysteomy bed recurrences. From what I recollect, it was less than 5%. So very, very low rates of actual in field recurrence. Most of those patients who had kind of recurrences, as we would expect. Bladder cancer are distant, right? These patients ultimately need some type of systemic therapy. And to your point, Cam, while the data for overall survival did show a separation of the curves, if you actually look at the overall survival curves, the KM curves come back together. What that tells us is that the major criticism of the study is the lack of immunotherapy and lack of modern systemic therapy. Why did the overall survival curves come back together? Just theoretically, and maybe just kind of maybe thinking of a reason why. Well, these patients ultimately had a lot of distant progression. And if they didn't have modern and very high-level systemic therapy, then that distant progression ultimately, even though we controlled their local disease, we didn't impact their distant progression. And that's what took their life. So that's where I say, and that's where I'm being very optimistic, is that with advances in systemic therapy, right? Antibody drug conjugates, immunotherapy, um, even chemoimmunotherapy, there may be a role for us in radiation oncology to impact patients' overall survival. You didn't see that in the study. You may not see that even with a five-year update, a four-year update of this FART study. But I I have a feeling that it's because of that exact reason that we may not see that OS benefit.

Immunotherapy ctDNA And Next Trials

SPEAKER_01 45:17

Yeah, that's a great, great point, Dr. Hansen Dada. Thank you for sharing that. Um I do have uh just a little bit of some literature that they gave us in the manuscript, um, which I thought was really interesting. Um it includes, um, I believe it includes the Egypt trial or the um Egyptian cohort with the um with the large proportion of squamous cell carcinoma. Um and there's uh the checkmate 274 trial, which investigated in the bowling lab. Um we talked a little bit about immunotherapy um as a future um option or uh something to look at in the future. Um, including immunotherapy, what do you think is what do you think is next for for these patients? Is it uh adding another line of therapy, like immunotherapy, to um to on top of everything, surgery, chemo, radiation, is it going to become more complex? Is there an easier answer? Um or is it ultimately just going to be uh intervention on on top of intervention?

SPEAKER_04 46:26

So, you know, when I think about the patients that respond well to immunotherapy, like how immunotherapy is coming into play for these patients with bladder cancer, and like Dr. Hasenzada said, it being part of the adjuvant or updated systemic option. You know, we also mentioned that part of the like a toxin that they chew, at least in this BART study, was part of um one of the etiologies that's a little different than patients here, and maybe that's why it's in younger patients. But similar to how we think of maybe HPV and responsiveness to things for head and neck and gyne, right? There's also new studies when for things like oral cavity cancer, where there's very advanced disease and certainly metastatic disease, how those patients are responding well or better with immunotherapy with ongoing analyses. And so this isn't similar kind of etiology, right? Where it's also a post-resection setting looking at high-risk disease. We give radiation for these certain risk factors, high-risk neural cavity that have a similar etiology. And it's not squamous cell, it's a different phenotype. But I think the important things as we try to add in these different modalities is to make sure we're not causing too much toxicity, right? Because a lot of those early toxicities for our patients are all inflammation related due to that radiation. So with respect to like, do we add it all on, you want to get the timing right so that they can tolerate the radiation, get get the immune checkpoint inhibitors afterwards without preventing them from being able to tolerate either or. Because I think, you know, with radiation, we can't always predict how much response patients are going to have or how much toxicity is they're going to have. And the same is true for immune checkpoint inhibitors. Um, where I joke a little bit that you want a little bit of toxicity with immune checkpoint inhibitors, but not too much toxicity. Because immune when you have a little toxicity, right, that means that your immune cell is activating against something, right? If it's too much toxicity, then you have to stop the treatment. Um so I think as we combine these, knowing that in separate situations of adjuvant radiation or adjuvant immuno, they both work. The right Goldilocks point is going to be adding them and having the timing right so that patients can receive them as needed, if if needed for high-risk cases, right, and allow them to get the benefit from both without toxicities kind of canceling each other out.

SPEAKER_01 49:05

Gotcha. Right. I hear a lot about uh like an interplay between um immunotherapy and in radiation therapy. What do you think uh of a future trial design would be um with respect to this trial? Um, do you think that there would be some sort of um synergistic uh trial design with radiation therapy and Ebola maps per se versus um what other kind of um comparator? Um would observation still be an adequate um control or um Yeah, what do you think research-wise is needed?

SPEAKER_00 49:48

Yeah, so I think um bladder cancer has has come a long way since the BARP study. Um you know, we talked about immunotherapy, we talked about antibody drug conjugates. So I think having an observation arm isn't really fair anymore. If you have this high-risk patient, you have to put them on either immunotherapy or uh typically afforded amounted and temperalism out BV Pembroke. Um, so that's your that honestly is your bar. You have to beat that, right? And how do you beat that? I'm not exactly sure. Um, you know, uh the potentially a good way to do it is we are using a lot of ct DNA nowadays. Um, so potentially you really want to select the patients who you worry the most about local recurrence. So potentially stratifying, and there's a lot of studies like this more in the definitive setting, not in the post-ystectomy setting for bladder cancer, but stratifying patients for C DNA positivity or negativity, and potentially for those patients who are positive, incorporating radiation as a way to address that disease. Um, you know, and it really, I guess, enriching for a population where we think radiation is going to make a big impact because we know bladder cancer has an ultimately a high rate of distant nets. But we've talked a lot today that local regional recurrence is significant, um, but it doesn't happen, you know, in necessarily a majority of patients. It just happens in maybe somewhere around 40 to 50 percent. And we need to just select those patients to find that benefit for radiation. So I don't know if Dr. Gensity has other thoughts, but those would be my initial thoughts.

SPEAKER_04 51:26

Yeah, no, I think those are excellent. You know, I think the hard thing with clinical trials, Cam, is we all want to figure out what the best treatment is for our patients, right? But as different parts of the needle or the treatment paradigms are moving at different times, right? A patient doesn't want some part of it to be subpar and to test out that part later. And this is like a common problem with trials, and sometimes, especially with radiation trials, why they may be um stopped early or discontinued is when like a standard of care change happens for the systemic therapy compartment. So, no, I completely agree with Dr. Haasanzada. Um, I don't know what the right answer would be, but we have a lot of really brilliant, even bladder expert radiation oncologists and medical oncologists who I'm sure can work together to make the next great trial for these patients.

Closing Takeaways And How To Engage

SPEAKER_01 52:21

Yeah, that was a really unfair question for me to ask you. So I appreciate your support uh and your willingness to try to tackle that. Um, this has been really uh enlightening for me uh when it comes to just the management of bladder cancer um and what the experts um say about um about this trial. I thought it was a really, really incredible trial with great results. They met their primary endpoint of um two-year local regional failure-free survival.

SPEAKER_00 52:54

I guess just one closing remark is if you're a medical oncologist or urologist that's hearing this, or if you're a radiation oncologist, I think this study gives you something else to put in your armamentarium to say, hey, adjuvant radiation has a benefit for patients. It's actually not very toxic. The NCCN has it as category two. So not a high recommendation, but it kind of I think they're hinting that there is a subset of patients that benefit. Um, so uh, and I I see actually these patients quite frequently. I've had a few referrals just very well today to say from my medical oncologist saying, hey, this patient has node positive disease. Would you be willing to see him and have a discussion? Um, try to decide between just giving him systemic therapy or adding radiation. So it's like it's a common thing that comes up. Um, and I just kind of want to advocate for the field of radiation oncology and say this is a study that I think puts us back in that conversation in many ways because of the low toxicity and the benefit with local regional control. Excellent points.

SPEAKER_01 53:55

Um, if anyone has any questions um or uh wants to potentially um have a suggestion for next journal club um entry, uh we'll put our contact info in the show notes. Um I want to thank uh Dr. Hasan Zada and Dr. Duzinski for being here tonight. And um thank you everyone else for joining in. Um, thanks for listening.

SPEAKER_03 54:26

If you liked our show, please subscribe and leave us a rate. We hope you're having a great day and look forward to seeing you again soon.