Chapters Transcript Video Trimodal Therapy for Muscle Invasive Bladder Cancer - Implementation in Daily Practice Girish Kulkarni, MD, PhD For me to have Dr. Kulkarni here, um, you know, our, we did residency together for those that you don't know, and our program is a 5-year program and you have an option, um, to go out of it after 2 or 3 years to do a master's. So I first met Garish when I was a medical student and he was a resident and I think on Mike Jewitt's service, um, but after your 3rd year, right, uh, you went into a surgical scientist, but Garish actually stayed up for 4 years and did a PhD in, in that time. Um, and then he's come back to, uh, the UHN and Princess Margaret has been really a thought leader in bladder cancer, um, has been a leader in their surgical leadership as well. He's the division of surgical oncology chief, um, and as he is a sitting, uh, chief of, uh, the urology program there as well. Um, and I think Garish has just, uh, done a lot in superficial bladder cancer. And um ladder preservation, which he's going to talk to us today about. And uh, you know, one thing I think I just, I'll say, you know, you lose touch with a lot of people after you finished residency and you go on a fellowship and academics and stuff like that, but Garish is one of the few people I always make a strong effort to hang out with, and we always get together all the meetings and you've been a real true friend, um, so it's an honor, Gerrish to have you speak to us today. Thanks, uh, Sano for that kind introduction. I would say the University of Miami groups probably the group in America. I know the best, interestingly enough, uh, because you're there, but also I independently got to know Dippin, um, when I was a fellow and, um, uh, at Memorial Stone Kettering, and I met him, uh, at one point. He started sending me a lot of JU all papers to review, and that's how I think our Our relationship kind of got going and then I met Chad and Mark as the years went on, Mark was actually uh the external reviewer for one of um my master's students. So, um, I'm always trying to maintain a connection uh with the Miami crowd. Um, so then Sana asked me, can you, um, uh, give a talk, give a CME grand rounds, and I said, sure. And um I thought it would be best to talk about um trimodal therapy. It's something that we've been using quite a bit in Canada. I think it's probably taking off now, I would think in all of North America. When we've published our first big paper, I actually came down to uh give a talk at the University of Miami on the South Beach conference, um, and that was my first foray into with your group, so it's good to be back, and that was 2017, so eight years later. Um, I was looking for photos. I'm sure I have some somewhere of Sanaj and I going out, uh, and I think, um, Koperberg was there too, but, um, I luckily for Doctor Punan, I don't have those. OK, so I look, I look just as young. You do. Um, here are my disclosures, uh, many of these are bladder cancer companies. And uh our objectives are to understand the role, uh, current role of trimodal therapy and bladder cancer and to update you on MIBC and also a little bit on NMIBC because you may hear um some of your colleagues in radiation oncology talking about it and uh I thought it'd be worthwhile to review that. We don't hear much about it in our um circles I would say in terms of NMIBC. So radical cystectomy I put down here, it's the gold standard for localized MIBC. I think it's the gold standard, certainly the most established. Um, I know my colleagues in radiation oncology here don't like when I call it the gold standard. They think I should be calling it a standard, um, but whatever nomenclature you want to use, uh, it's been around a long time. It has a proven track record. You can get, you, you get accurate pathologic uh sampling, you get nodal sampling, you know the uh exact stage, uh, when the bladder has been removed. Excellent local control, durable survival. So we know this is a great modality for patients with localized MIBC. The problem is, um, uh, in 20 since the turn of the century, um, we have understood in America and it's very similar data in Canada that it is underutilized. These are older data, so John Gore's data and then corroborated a few years later looking at uh utilization of cystectomy or chemorads for localized MIBC. And the top line shows on the right hand side, 50% of patients, when you look at NCDB data, just get nothing. They get surveillance, um, and surveillance isn't a known uh treatment uh entity for MIBC. Um, I would call that more palliation. It's not like active surveillance for prostate cancer. And then if you look at the histogram on the bottom, um, the blue blue blue bars represent the number of patients receiving, uh, quote unquote surveillance or no treatment, and naturally as one ages, uh, and you see the population getting to 80 to 90, uh, far less treatments are happening, um. Patients may not want to undergo a surgery, given their age and comorbidities at that age, uh in that age bracket, but one could assume that radiation should be something that is tolerable to these patients, and our most recent data from Canada from two years ago showed the same thing. Our surveillance rate or non-treatment rates is about 50%. And part of this, um, uh, is because cystectomy historically has been a morbid operation with uh mortality rate associated. These are older data from Memorialsone Kettering, uh, looking at over 1100 patients and 64% of their patients had Clavi in grade 2 to 5 complications, um, and, um, they had a high readmission rate of 25% and our Nqui data in Toronto suggests the same. Um, mortality is anywhere from 1 to 6%, and in ages 80 and up can be up to 13%. So when this is presented to patients, they may think twice. Um, quality of life, um, historically has also been an issue, and on the top you can see, um, quality of life measured pre-op at 3 months at 12 months, um, in terms of physical and role functioning with cystectomy, um, the, the red dots represent the red lines represent conduit patients. Uh, the physical and role functioning diminishes. Global quality of life is pretty stable throughout. And I think with robotics, we may be helping patients um uh uh recover and achieve their baseline quality of life. So a lot of these data are also older, but nevertheless, even if I offer robotic cystectomy, I do find it's not um a surgical operation that patients are jumping at if there is a bladder preserving option. Um, and then, of course, there's long term postoperative complications such as uh sexual dysfunction. Uh, and potential, uh, strictures, um, and tubes that may be required, bowel obstructions, sepsis, etc. that can happen with, uh, cystectomy. Uh, patients also lose a fair amount of weight, um, uh, a na 2 months of anywhere from 10 to 20 pounds. Um, and so the way I usually think of this or frame it is there is short term pain for long term gain. So that's where trimodal therapy comes in, uh, which is maximal TRBT, chemotherapy and radiation. And I think of it as two distinct groups. There's the group that's unfit for surgery, so in that histogram I showed earlier, patients who are 80 or 90 years old, maybe, uh, we don't want to bring those individuals to the OR. They don't want to come to the OR, um, even if we're the, the best surgeons that you never know what's gonna happen to an individual like that and one hit can really impact them. So rather than treating none of those patients, this gives us an opportunity to treat more. And of course, we have a number of patients who are younger in their 50s and 60s who are looking for bladder preservation. And so the concept here is maybe in select patients we can maintain quality of life and not compromise oncologic outcomes, and I think the latter is the most important aspect. Um, at the University of Toronto, our ideal patients for trimodal therapy are those with smaller tumors. Our initial publication, we said 5 centimeters. Uh, a recent publication, I have one slide on it from Doctor Zlata and, um, uh, Doctor Estacio from MGH picked 7 centimeters. So when I say small, these aren't really that small, like 7 centimeters is a pretty big tumor. Um, unifocal, uh, no hydro or minimal hydro, minimal to no CIS, they have to have good bladder function and capacity. Uh, there's no point of trying to, in my opinion, save a bladder that has a 50 cc capacity and the patient is up, uh, 7 times at night. Those are the patients on post-op day one, as any of us who do cystectomy know are the most grateful because they got a good night's sleep. Um, so, um, you need to have reasonable function to, to be a good TMT candidate, and of course compliance because the bladder is maintained, so we need to be able to scope these individuals and make sure they don't have local recurrences. Um, two different approaches, uh, the approach on the left has become, I think, more standard, uh, MGH on the right hand side. Uh, use a split course approach whereby they would give induction radiation 40 grade with concurrent chemotherapy, then assess with biopsies and if there's an incomplete response, then a patient would move on to cystectomy. But if there is a complete response, then they would, uh, consolidate or finish the radiotherapy treatment. And I think that was more of a historical issue because when they were using primodal therapy, I would say they're the pioneers in pushing the envelope in North America. Um, they received a lot of pushback from the urological community, so they didn't want to compromise oncological outcomes. But nowadays I would think of this as trying to do a prostate biopsy in the middle of um radiotherapy for prostate cancer. It doesn't make sense. You have to wait. So that's what we do on the left hand side, that's continuous course. So patients get their full course of radiotherapy with chemotherapy, and then we assess um for either complete or incomplete response. Incomplete responders can move on to salvage cystectomy. It really depends on what um their staging demonstrates afterwards, and I'll talk a little bit about that later. Um, this is a trial published in the New England Journal of Medicine, Nick James BC 2001, and it was basically a trial of radiotherapy versus radiotherapy plus chemotherapy for MIBC and demonstrated um much improved disease-free survival with radio sensitizing chemotherapy. At the University of Toronto, we use cisplatin at 40 mg per meter squared, so it's a lower dose than uh one would receive with um uh chem and cisplatin and the new adjuvent or the induction uh setting, um, and this study was 5FU mittamycin. Um, gemcitabine alone can be used as well, um, but primarily we've been using cisplatin. In terms of outcomes, and that's the, the, I think the most important aspect here we're bringing in a new technology or newer technology and newer approach, we need to make sure we're not harming patients. Um, MGH published their outcomes, the initial set, so this is from 86 to 02. So these are older data, 348 patients. Um, median age was 66, and their 5 year OS and DSS was were 50% and 60% respectively, 10 year, 35 and 60%. So not the greatest really in terms of contemporary numbers that we would expect and their salvage cystectomy rate was 30%. But they persevered and pushed on, um, and published more recent data and so that's what these Kaplan Meyer curves are, are demonstrating, um, and the red curves are the most contemporary data they've presented, uh, published in European Urology, and you can see they've improved significantly with 5 year OS rates of 75% and 5 year disease specific survival rates of 84%. So these are more in keeping with what I think we would see in the cystectomy world. So I would have expected for a patient who would have localized disease, T2, clinical T2, um, we should be having a disease specific survival of over 80% uh for these individuals, and, uh, I would say close to 85% to 90%. Now, um, the, the salvage cystectomy rate is the bottom right histogram, and they went from 30% down to 15%, and the way this all happened is, uh, patient selection. So here are the patient characteristics, uh, in the most contemporary cohort in the right hand side where I have the red circles. And on the left hand side, 86 to 95 when they weren't having results that we would deem uh acceptable uh in if cystectomy is eligible for uh is available for patients. And uh what I've circled is uh the T stage. So back in '86 to 95, many of the patients were T3, T4, up to 60%. But uh in the more contemporary data set 5 to 2013, 97% were clinical stage T2, um, hydronephrosis, no patients had hydro in the more contemporary, uh, series, uh, CIS much lower rates in the contemporary series, um, and, uh, TRBT, uh, visibly complete TRBT, so removing all microscopic disease, much more common in the, uh, contemporary series. So, uh, essentially, if you will, the term people have used, I think, in a negative connotation is cherry picking, but I would say this is appropriate patient selection because if we select these patients appropriately and can get similar results results of cystectomy, then we have another option that's available to patients. So if we have two modalities, can we do a randomized control trial? It was attempted, uh, the spare trial, uh, by Doctor Hutter and colleagues. It was a UK based feasibility trial. uh, it was supposed to be a non-inferiority trial. Ultimately they want to randomize over 1000 patients for this to work and so they ran this feasibility trial that would be rolled into the non-inferiority trial aiming to get 110 patients in 3 years and I thought if they could randomize 110, then OK, they can move on and actually expand this and, and I think we can all acknowledge that the uh uh Brits, uh, the British uh urologists and oncologists are probably the best in the world at. Pulling off some of these trials in terms of um uh radiation versus cystectomy. So surgery versus non-surgery, um, uh, comparisons. Over 30 months, so almost 3 years, they only managed 45 patients, so they were halfway, uh, in terms of their feasibility target, and they had a 24% noncompliance with treatment assignments, so they pulled the plug on this trial. So unless something changes drastically, I don't know and I don't think we're gonna have a randomized trial moving forward in this space. So that's why we have retrospective analysis and we published ours first one back in 2017. Um, and it was a small series, but, uh, one of the larger, better done studies at the time. So we managed to publish this in the Journal of Clinical Oncology with about 120 patients, so 60 and 60 matched. Uh, many were eligible for cystectomy, but they chose in our center to undergo trimodal therapy, and here you can see the Kaplen Meyer curves and cumulative incidence curves for diseases specific survival. Um, we had a medium follow up of 4.5 years, and the 5 year disease specific survival was quite similar between the groups, 76% for TMT and 73% for radical cystectomy, and we had a salvage cystectomy rate of 11%. Then Doctor Zalatta, um, who is one of our, um, champions of trimodal therapy and really interested in the space, he works closely with Jason Estao. They put together a three institution series, so our institution, um, of, uh, trimodal therapy and cystectomy with USC and MGH. So our institution contributed to both categories. USC contributed to the cystectomy group and MGH, the trimodal therapy patients. So basically, um. In theory, amongst the better surgeons or best surgeons and the best radiotherapy to compare, um, what are our outcomes in a propensity match analysis in the largest subset of patients. Again, retrospective, 722 patients though, so a fair number, and their outcome was metastasis-free survival and um you can see on the left hand side uh and with um uh propensity score matching inverse probability uh treatment waiting. The curves are almost exactly overlapping. Um, and I guess uh I should update the bottom right. It has been published in Lancet Oncology in 2023. Does TMT come with toxicity? Uh, the older RTOG trials from the early 90s uh demonstrated no treatment-related deaths, no toxicity um related cystectomies and those series, the grade 3 plus GU complication rate was 6%, grade 2 GI grade 3 plus GI complication rate was 2%. Um, the MGH group published their complication rates after salvage cystectomy, um, and they had 91 salvage cystectomies, and remember they started off with this split course radiotherapy approach, so 50 patients would have an immediate cystectomy, having undergone just some of the radiotherapy, whereas the other 41 were downstream. All these patients received allal conduits. They did have a higher proportion of tissue healing complications, so ureter, um. Uh, urero intestinal anastomotic strictures, um, Uh, wound de histances, etc. with with a salvage in the salvage setting compared to a primary uh setting. So this was salvage cystectomy after uh radiotherapy for TMT versus uh cystectomy in a retrospective uh uh analysis. They updated their data and just to walk you through it, the top left box, um, are early complications less than equal to 90 days, and they looked at three categories, primary cystectomy, so someone comes in, muscle invasive disease, localized, they go straight to cystectomy, plus or minus neoadju chemo, um, salvage cystectomy after a TMT, small cohort, only 21 patients in this analysis. And then they also looked at another group of patients that underwent a uh primary cystectomy, so no TMT but they had had previous radiotherapy for other malignancies, for example, cervical cancer, colorectal prostate, uh, any pelvic uh radiotherapy that was not for bladder preservation. And um ultimately the rates of complications were higher with salvage cystectomy. um, they had higher respiratory infectious rates in the early going and neurological. I don't know if some of that is those are just spurious findings and by chance, but the bottom left box is the late later complications and again more infectious and gastrointestinal uh complications with salvage cystectomy patients compared to primary. Uh, and more genitourinary complications, so 26% genital urinary complications, that would be mainly stricture, sal stenosis, things like that, um, urine leaks, um, uh, post, um, cystectomy compared to a primary cystectomy. And the histogram of the top right here demonstrates the same fewer complication rates in terms of uh early cystectomy with primary, um sorry, fewer complications rates with uh uh primary cystectomy compared to salvage cystectomy and that panned out also in terms of late longer term complications with Kaplanmeyer analysis. So based on these data, when we offer someone trimodal therapy, if they need a salvage cystectomy. Um, at our center, our policies do not offer a neobladder or a continent diversion, so that goes into the patient's decision making process. I know there are series, for example, from USC where they have demonstrated this to be um safe. And uh feasible, but, um, our concerns are always strictures and using radiated, uh, potentially radiated bowel and ileum for continent diversion. So if someone goes for TMT and they did a cystectomy, the 10% downstream, we offer them a conduit only. Ultimately, um, because of the oncological outcomes and the options available to patients, uh, TMT is guideline endorsed by every major guideline. Um, the EAUAUA and CUA and in the updated guidelines as well. The next part of the talk, I want to talk about some practical aspects to implementing TMT, um, so we do this in a multidisciplinary fashion at the University of Toronto, we have a multidisciplinary bladder cancer clinic we call the MDBCC, and it's been in place since 2008, and it's primarily patients who are interested in bladder preservation. Or follow-ups of those individuals, but we will see in a complex um uh NMIBC or metastatic patients there as well as needed. Um, and we do the clinic with a rat on, so the radiation oncologist is with us, they come in the room we're scoping, um, it's helpful to, to us because That and the radiation oncologist because they see where the tumor is, uh, which is important in terms of treatment planning. Um, and it does provide for an interdisciplinary discussion. The patient, uh, basically gets a bedside tumor board right then and there. Um, we have a clinic coordinator who helps us put together, uh, notes, um, especially for external referrals where you may get a referral with 30 or 40 or 50 pages, um, or, or PDF pages or multiple documents, so they help us, uh, uh, consolidate all that into one note. So it helps us get through the clinic and a more expeditious manner, um, and we scope at the same time as doing the consult. So the advantages are uh simultaneous assessment, so easier on the patients. Um, I think the biggest advantage is reduction of bias because you won't have a patient getting into a scenario where the surgeon says, no, this is the best way to go, um, there are no other options, forget radiotherapy or the radiation oncologist saying, well, no, radiation is the way to go. It's uh it's much better, better quality of life. You have more of a um. I think unbiased level headed conversation and the patient sees that it's patient friendly, better communication between specialties because we're all on the same page and um two or three heads are better than one. Sometimes you may miss something and uh you have a colleague who can say, well, maybe we should try this, and you're bouncing ideas off each other. In the past we used to actually have a piece of paper like this. We still actually do that summarizes everything. Now with our electronic EMRs and Epic, um, many of these patients are pre-charted, so it's just electronic uh as opposed to paper, but it's still, um, this gives it an idea of a patient journey that we don't have to fill in. And I told you we do continuous course, uh, uh, trimal therapy in Toronto. Um, and basically a patient is seen in our clinic, we are big proponents of neoadjuvant chemotherapy, and I have a few slides on that coming up. Uh, we would do a debulking TRBT, um, if there is a fair amount of residual disease after chemotherapy or if they're not eligible for chemotherapy prior to embarking on the radio therapy aspects. Uh, we use fiducial markers in patients where, uh, we think it'll be difficult to target, uh, and treatment plan, and we use lapidol for that. Uh, in the past we would do 40 gray to the bladder and pelvis and 26 grade of the tumor. Now we're hypofractionating so our treatments are done within um 20 days of treatment and like I said, 40 mg of uh permetus gra cisplatin. This is what our fiducial marker is. It's called lapiol. It's an iodized oil derived from poppy seeds. So in Canada, this is $300 a vial. Uh, it's 10 ccs. You do not need 10 ccs. that would treat 10 to 20 trimodal therapy patients. Uh, you only need 0.5 to 1 cc. If you put too much in, it looks like um. Uh, a radio opaque explosion in the bladder, uh, and I'll show you a picture of, not that, but what it looks like when you put the right amount in. But if too much, uh, is placed, then the entire bladder and pelvis and surrounding area just becomes white on a planning CT so it's not useful. Uh, we use a uh flexible cystoscope, uh, 27 gauge, 105 centimeter um Olympus needle. Um, the needle is 4 millimeters and you can see it in the top right. That's the oil droplet, um, and you can see a little bit of the needle coming out. This is all done under local, uh, with no anesthetic, save, uh, xylocaine jelly because, um, it's well tolerated, it's not painful. Um, And we look for the scar for patients who are post, uh, neoaggen chemotherapy. So many times we don't even see a uh a resection bed. We just see a scar and we'll eject uh circumferentially around that area. Or if there is a resection bed you can see here, we would go about 1 centimeter or 0.5 centimeter around it so that the radiation oncologist can then see um uh where to provide the boost. So our, our group usually this whole bladder with a tumor boost. Uh, why do we do this? Because it enables us to, uh, uh, apply image guided radiotherapy. Um, there are, uh, possibilities of infraction motion. The bladder position differs differs every day. Uh, it may be more or less distended, stool and gas can change the setup, um, and there may be inaccuracies in, in how the patient is, uh, uh, set up and positioned. So this allows for um a more adaptive radiotherapy approach. Uh, this was, um, an inter-observer agreement study of three radiation oncologists, uh, who were treatment planned in bladder cancer with and without lapiol. It was a small study, 5 patients, but if we had a fiducial marker in the amount of overlap for the treatment volume for the boost was actually much better um than without and just going on, um, the thickness of the bladder on a uh planning CT. And it was found to be more accurate than bony landmarks as well. So this is what the lapiol looks like. You can see on the left-hand side, it's been injected around the tumor site. Um, many patients can have bladder thickening, so where does the radiation oncologist, uh, need to concentrate? Um, the, the boost, so the lapiol actually helps quite a bit, and if this is only give it putting in, like I said, 0.5 to 1 mL if you put a lot more, then uh the entire in this patient, left side of the pelvis uh would look white and it'd be hard to plan. And here's another example of uh a radiation oncology plan for bladder preservation. So we use the piol because it's easy to see. Um, it does last. Uh, one of the knocks in theory against it is that it wouldn't through the treatment course, but we don't, we've never found that to be the case. In fact, we sometimes see patients coming for a CT for their follow-up, and they have a CT at 3 or 6 months, and the radiologist will comment on calcification in the bladder wall. That's not calcification, it's actually our traditional marker that's slowly absorbing. Uh, you can use gold seeds, um, and I've talked to our radiation oncologist about this. They their feeling is that they just fall out, so you, you insert them into the bladder wall, but they'll, they have a high uh tendency of just being extruded. An endoclip can be used as well. Um, I, I found a paper on that and the problem is to put an endoclip in. Um, certainly the way it was described, you need a rigid scope, which is not, um, pleasant under local anesthetic, that's more of a 1980s thing I would say, uh, and you'd need to have other sedation or um a GA to actually do that in a, um, I guess, reasonable manner. And we have on our wall our follow-up schedule so that even when we have new residents uh or or fellows come in, they can see um how we follow our patients and where they should be um in their patient journey, what should be the next step, um, so it helps with the turnover that we have in clinic. Now just a few examples of pictures. So this is a patient post neoaggen chemotherapy. We wouldn't simply go on to try modal therapy for this patient, we would debulk them and remove this uh unusual looking tumor. Uh, post TMT you can have, um, bladders that look like this. Um, this is not the best example. I have even worse examples of dystrophic calcification, um, or, uh, continued fibrine, um, uh deposition in the area of the TMT and previous tumor. So the, the bladder after TMT takes a long time to heal. Um, so I would say it takes sometimes 6 to 12 months for it to look normal. And we, once the patient undergoes TMT, you just have to get used to that concept and understand, uh, with experience what is normal and what is not. And of course, we're used to seeing uh radiation cystitis, and that can happen as well. Um, I think it depends on who is actually giving the radiation and the treatment planning because many of our centers outside of Toronto are now giving trimodal therapy and um I've operated on some of the patients after they've received trimodal therapy outside, and I've noticed a difference in terms of uh tissue planes. I, I, I feel like our group is very experienced in planning and providing appropriate dosage. Um, how much time do I have? Let's see, 34. OK, I'll try to go through this part somewhat quickly. Uh, I have identified about 7 or 8, controversies, updates, um, or, uh, topics that I would like to address. Uh, and I'll go through them. I have a few slides on each. So, uh, the first is a population-based studies. You'll see a lot of studies out there in the trimodal therapy versus cystectomy literature, and almost all the population-based studies demonstrate, and here's one example from Quattrin and Thomas Season, um, improved outcomes with radical cystectomy, but these are database studies, uh, SER and CDB, and usually historical, uh, patients. Who would have um uh had radiotherapy, I think in more of a palliative setting or that could be the worst actors. Uh, we don't have granular data on carcinoma situ or hydronephrosis, the quality of the TR or why the patient even got, um, radiation. Are they unfit for surgery? Was it really a true bladder preserving approach? So I think all of these uh studies have to be taken with a grain of salt. Uh, we did a systematic review and meta-analysis looking at. Uh, results from, uh, population-based studies that's in the top left, um, and single center studies again the top left, so the top 4 are single center studies and the population-based studies are the bottom 5 there. And if it's a population-based study, they generally favor radical cystectomy. Single institutions tend to uh be neutral with not one group uh favored over another, and I think that's because of the bias in some of these databases. What about neoadjuvant chemotherapy? I told you that we use that in our uh TMT uh treatment algorithms, and that comes from the concept level one evidence of neoadju chemotherapy for radical cystectomy. We've adopted the concept that neoadjuvant chemotherapy should be given to manage micro metastatic disease, downstage the disease, and then the patient will choose the radical therapy that they, uh, want. So a patient is a poor responder to neoadjuvant chemotherapy, we'll often push them towards radical cystectomy, but we do have some individuals who are just phenomenal uh response responders and their tumors are extremely chemo sensitive, um, and until we can figure out which patients to just spare any treatment, and I know those trials are going on, um, retained to modern, etc. We've been offering radiotherapy as a, a, a bridge, and that's been working quite well for us. So the chemo also helps us select patients. Um, and so on the left hand side, you can see, uh, or this is another way of showing our algorithm, you had chemotherapy at the top. Um, we usually will image midway to make sure a patient's not having progression. They would get 4 cycles. Uh, our, our medical oncologists like Jemsis, not Dosan MAC. And then a patient uh with stability or response will then move on on the left hand side there, uh to uh external beam radiotherapy. Um, neo chemo, um, I, I think there's some evidence from older data. This is the old MRC CMV data, um, of, uh, almost 1000 patients, um, and on the bottom left you can see overall survival with neoadjuvant CMV versus not, and that was statistically significant in the cystectomy population hazard ratio of 0.74 P value 0.02. In the subgroup looking at radiotherapy on the right hand side, uh, the hazard ratio is 0.8 in favor of neoaggen chemo. The P value is not quite there, 0.07, but it's pretty close, so there's a strong trend and the Kaplan Meyer curve looks almost superimposable. So our feeling is that uh this uh the the right hand side may simply be underpowered. Uh, we used our Canadian database, uh, West Casoof did to look at 586 TMT patients. 102 received neurgent chemo, and this is across Canada, um, uh, study, uh, so every center contributed, uh, patients, and we, uh, performed propensity score matching, and those individuals who had neogen chemo had much improved cancer survival and overall survival. And you could say, well, this could also be um. Uh, uh, because of selection, but, uh, these are all TMT patients. We're not necessarily comparing here to radical cystectomy. So it's TMT patients with and without uh new urgent chemo, and this changed the approach of the McGill group. Now they use new urgent chemo, and most of us in Canada are doing that. do some markers I talked about, so I won't go over that. Necessity of post TMT biopsy. Um, I think the bottom line here just for time is we do not do a post TMT biopsy unless the cytology is positive or we see something abnormal, just like any surveillance cystoscopy for non-muscle invasive bladder cancer when we're surveying our patients. If it looks abnormal or we have worry, we would do a TRBT or a biopsy. That's a no-brainer. If it looks completely normal, we simply monitor. The McGill group doesn't, um, if it looks normal and that's the uh right hand side of this um set of boxes and flow flow diagram, they had 140 patients with non-suspicious assessments on normal cytology, normal cystoscopy, um, 56 underwent a biopsy and 84 didn't, so they're not doing it on everyone. So something must have prompted the biopsy and even then. When they did do the biopsy of the 56, um, they did find tumor in 9 patients, 3 were muscle invasive. Ultimately, our feeling is that we're following these patients pretty closely. So, um, if there is something there, it will declare itself. So we have not adopted the post TMT biopsy approach, but I think that is still um controversial. How do you manage local recurrences? Um, I've presented these data before in our initial series we have 56 TMT patients. Um, 60% did have recurrence, and about half of those were local intravesicle, half are systemic, and of the locals, most are, uh, we can manage endoscopically. Uh, most are non-muscle invasive, um, and because many of the patients haven't progressed from non-muscle invasive disease to muscle invasive disease, uh, majority that we see are de novo, localized MIBC. They're primarily BCG naive, so BCG actually does work quite well in an NMIBC setting post TMT, and that's what we looked at here. This was a match analysis of NMIBC recurrences after TMT, uh, so on the bottom left. The cumulative incidence of uh recurrence, um, treating them with BCG that's the uh the yellow line. We don't have a long long follow up for these patients because there aren't a lot of them compared to matched, uh, walking through the door, NMIBC patients, and in fact the TMT patients who have NMIBC um managed with BCG actually do quite a bit better than um. De novo NMIBC patients coming in, which was interesting. And again, some of it may be selection as well, but certainly they're not doing worse and I don't think you need to do a cystectomy if someone has a TA high grade recurrence or CIS. And the Mass General Group have also looked at this as well. Um, they had 475 TMT patients that they assessed. uh, uh, 3 quarters were complete responders and of those, uh, three quarters of 342, 25% had uh NMIBC and the distribution of stage is listed there, primarily TA high grades and CIS patients. Um, the T1 patient, they had 20%. I think that type of individual, you have to have a serious conversation about having a salvaged cystectomy. Uh, we, many of our patients who do have a recurrence in their T1 have still wanted a re-resection and bladder preservation, and we'll offer that to them. Um, what about variant histology? Not a lot of data on variant histology. Again from Mass General, they looked at 303 TMT cases, uh, over 20 years, and they only had, um, 66 variants. Um, the vast majority of those were just very, uh, divergent differentiation. So in terms of true uh subtypes, there weren't a lot. There were 8 sarcomatoids, 3 micropas, uh, and some 1 nested, uh, one nested in glandular, and a few neuroendocrine. So not a lot of really bad acting players here. Um, nevertheless, when they assessed the pure urothelials versus the variants, no difference in terms of, uh, bladder intact disease specific survival, disease specific survival or overall survival, but the caveats are small numbers. Um, the degree of variant histology is at 10%, 5%, or is it 90% is lacking, uh, because this is a retrospective study. The recognition of variant histology, I, I, I had questioned in 1993. How many pathologists were actually identifying micropapillary disease, uh, so I think we need to have a more modern, uh, updated assessment. And remember, the TUR histology isn't always the cystectomy, uh histology. Um, we do know that if the pure histology is different, this is looking at urothelial carcinoma of the bladder versus neuroendocrine versus squamous versus adenocarcinoma. Um, I think the data are a bit more robust here. This is a SES study, and the green line is, uh, squamous cell carcinoma treated with trimodal therapy, and uh those patients don't do well with TMT and we don't offer TMT to our pure squams. Quality of life. Uh, again, I think this is an area for research because there isn't as much out there as you would think. Uh, early on, uh, around 2016, 2017, 2018, there was basically very few studies. This is a cross-sectional study, where patients were given a questionnaire either seven years after cystectomy or 9 years after TMT, and they found that the TMT patients had significantly better quality of life in terms of physical, uh, role, emotional, social functioning, etc. But this is uh this is basically, uh, there's a lot of selection because you're picking the best players at 7 and 9 years. It was more of a conditional survival, uh, type of, um, study, um. Mike Fairstein was a fellow at MSK and then he uh moved on to practice, but when he was there he reviewed the data on quality of life and TMT and bladder preservation and found only 4 retrospective and 2 prospective studies at the time. More research is needed. More has come. The these are the patient reported quality of life outcomes from BC 2001. This is the study of radiotherapy versus radiotherapy plus chemo that I presented earlier. And so this is not a comparison to cystectomy, it's just adding in the radio sensitizing chemo, did that impact outcomes? And you can see the curves are overlapping in terms of changes in quality of life. There was a decrease in quality of life uh during treatment regardless of the, the group, but um overall patients recovered to baseline. This was a study that Dan Joyce just published in JAMA Network Open a few weeks ago looking at the cost effectiveness of trimodal therapy versus cystectomy, and I've circled here qualities, which is the metric, uh, can be used for quality of life adjustment, uh, so quality adjusted life years, and in their study trimodal therapy at 5 years and 10 years had better quality of life. We also had done a similar study uh back in 2021. And our findings do corroborate with theirs, but we looked at stage, uh sorry, age at um at treatments in this modeling exercise. And so we found that younger patients had actually better quality of life if they had cystectomy. And I think it's because they can get through the operation better and then they have a lot of uh life expectancy and um once you get someone through the first year, uh, they often get back to baseline. And patients with, uh, who are more elderly had better quality of life with trimodal therapy. So I think something we would have expected, uh, makes common sense, like an older patient may not get through an operation as well, so they may do better with bladder preservation for quality of life, but younger patients will have in the long run, better quality of life with a cystectomy. Uh, we performed a prospective study at 3 centers, 400 patients, um, looking at utility data, uh, which is a quality of life measure, and we use the, uh, our own homegrown instrument bus, the EQ 5D and the QLUT C10D, which is part of the ERTC, um. Uh, I guess armamentarian quality of life instruments and ultimately, uh, we found that trimodal therapy patients had slightly better quality of life, uh, in their treatment phase, so in the 1st 6 months, and, um, in the long run, um, a few, uh, bars over, we have post cystectomy and post trimodal therapy that seems to be maintained in the long term. So, um, ultimately the data either point to. Um, slightly better quality of life with trimodal therapy or at least very similar. Um, and I, I, this study, the CISO study was presented at AUA. It has nothing to do with trimodal therapy and radiation, but it does make it did give you pause for thought in terms of, um, Bladder preservation, does that necessarily mean you're gonna have a better quality of life? Because in this study, they found that radical cystectomy actually could have better quality of life depending on, uh, compared to intravesical therapies and NMIBC uh compared to trying to save the bladder. So it made me think, um, is quality of life really much worse without a bladder and to save the bladder really preserve quality of life. So I think we need to do a bit more work here. Finally, NMIBC, um, I'll just take a few minutes here and I'll finish off for questions. Uh, what is the rationale? If we're gonna offer upfront cystectomy or Um, an early cystectomy in T1 patients, which is radical therapy, why not radiation? We started thinking about this a bit more during our BCG uh shortage. Um, we don't have a BCG shortage anymore in Canada because we have two varieties. We have uh two strains, variety and ice, but, uh, I know that there is still ongoing BCG shortage in the states. Um, so we, we discussed this a lot as a group about should we just be offering these patients, uh, TMT. Um, the issue is there's not a lot of data in the T1 and the NMIBC population. So this is a meta-analysis of uh of studies looking at TMT, uh, or radiotherapy alone in patients with NMIBC. You can see the studies are small. There's a few that are in triple digits, but some are 11 patients, 17, so small studies, um, almost all are T1. Uh, I don't think any of us would offer TMT, uh, to a TA high grade patient. It doesn't make sense. Um, almost none of the studies had CIS. Some of the studies actually used uh hyperthermia. We, we don't have that available in Canada, and I don't think anyone in America is using it. Uh, the radiation dose is approximately 50 to 60 gray. And uh the outcomes are pretty similar in terms of outcome assessment. So no visible tumor on scopes. Um, some patients would get biopsies, uh, negative cytology and some of the more recent series. So, um, when I was thinking about this paper, it's unclear and it wasn't, uh, published in the paper or written if the patients were recurrent or naive patients, um, meaning are these BCG unresponsive patients that they included? And uh it was a historical series they probably didn't even classify the patients as such. Many of the studies are poor quality, single institution retrospective small. The worldwide experience that was published, um, and I reviewed this just a few, uh, last year in the fall was 746 patients, so not a lot of TMT experience in this patient population. The salvage cystectomy rate in that meta-analysis or systematic review um was 13%, 5 year uh RFS 54%, and the cancers specific survival 86%, um, which may not be that bad actually considering it's a T1 population. Um, this study got a lot of, uh, I think, uh, airplay. It was just published in September, October of last year. Um, the NRG RTOG 0926 study of BC unresponsive patients, they not all of them were, but they were treated with trimodal therapy. It was a small single arm phase to 37 patients. They used either cisplatin, 5 of you and mytamycin for radio sensitization, um, and it came from uh MGH, so a good uh TMT center. And their primary outcome is 3 year freedom from cystectomy, which I don't think is a good outcome to be frank, because there's so many factors uh that dictate whether a patient will select cystectomy. They had a 3 year overall survival rate of 69%, 5 year 56%, but the grade 3 AEs, 2/3 had a grade 3 AE which is pretty high, uh, considering it's an NMIBC cohort, um. And then finally, uh, they had a 3 year cumulative instance rate of about 30% in terms of recurrence. Um, I'll skip this, and, um, just in terms of the future, um, I think we need to have better biomarkers to figure out which patients will respond, um, to trimodal therapy best, um, and which molecular subtype actually is the best responder to TMT, um, there are some data on the subtypes, but we are not using genomic classifiers certainly in um Canada. To help guide our treatments for TMT and some of the predictive biomarkers that have been thrown around, uh, with some evidence but not a lot of publication or MRE 11 and KI-67 expression. um, I don't know how to use these even if they were available in uh patients for TMT right now because I think the data are sparse. We need a bit more information I think on quality of life, um. And of course clinical trials, there are a number of important clinical trials going on. So yesterday I chat GPT it um and uh we all know about the NRG swag 1806 trial, that's uh TMT plus Teso versus TMT alone, Keynote 992 with Pembro. um, there's an adaptive versus standard radiotherapy trial and one in variant histology. So these are the ones that I think. Um, we're, uh, we will help inform our future practice. So in conclusion, um, I think that bladder preservation is becoming, becoming in quotes, I think it's here actually. It is an established treatment for localized MIBC um in selected patients with MIBC it yields outcomes that are as good as cystectomy, uh, so we should be talking about this, uh, with our patients and certainly if you ever go to any of the uh beacon meetings, um, that's one thing that patients are really, um, Uh disappointed at if they have had a cystectomy in the past and we find out they've been that TMT was an option or it was never discussed with them, and they may not have been a good candidate, but at least the understanding the concept, um, and I think there's still many unanswered questions we have opportunities to grow and learn, and I always put a plug in for our our fellowship. So if anyone, uh, uh, residents graduating from your program is are interested in. Uh, coming north, uh, and skiing and enjoying hot, humid summers, um, then come to our SUO program and apply would be interested. Um, that's it. I, I, I think I've left some time for questions, not a lot, so if there are any, I'll stop sharing. Hey Girish, great talk and thanks for, you know, covering so much in that. You guys obviously have been thought leaders in this field of, you know, bladder preservation and you have a large series, and I imagine many of the TURs that are being done may have been done, not necessarily at your site, right? They're done at community sites and then they get referred in. But what are you guys doing like in the, like I guess in translational research in this space like you talked about some biomarkers that are out there and that you may not be necessarily, but like are you setting up a biobank anywhere? Do you guys do MRI and looking at like radioomics, like, you know, other than the clinical features that you used to select, what are you guys looking at like research wise? Yeah, it's a good question. So I would say one of the downsides of our program for the longest time is we didn't have um A translational or a basic science program investigating um any outcomes in any of our disease sites. We had a few people dabbling and ours was more of a trials and clin Epi based center, if you will. That's changing because we've hired an individual who um is a scientist, as a surgeon scientist. His name is Keith Lawson, he did the his SEO fellowship at the NCI and came back. So he's starting up, um, translational programs in bladder cancer and in kidney cancer. He just came a year ago. He's more interested in cell-directed therapies, I would say. Um, we, um, are always bio banking, so urine, blood, and we have access to tissue. So I'm hoping that with his presence now that he's established himself here, we'll be able to look at some more. Um, I guess molecular features, translational features, and expand our, our basic science footprint in this space, because you're right, we, we do need more of that, um, and I feel like everything we're presenting and you're seeing out there is very clinically oriented. Yeah. Um, the other question I was going to ask about was, you know, your bladder cancer clinic, or I guess it's a muscle invasive bladder cancer clinic. So, you know, when I was doing residency, I don't think that was there, and I think, you know, you and Zlata are really to be commended in getting that going now. I know that just from a typical urology kind of week is like, you know, there'll be, you know, days in clinic days in the OR, and usually there's like a cisto day, which is, you know, the whole day you're just kind of doing systo. So finding the resources to kind of make this available, you know, for this clinic, I think can be a challenge. Like, and you talked about a lot of the good things about having it, but I'm sure there was a lot of challenges just in terms of compensation, like making sure your time is well spent there. Can you speak to that a little bit and like what it was like starting that clinic? Yeah, so I think it started when we were residents actually, and it was supposed to be a fellow only clinic, so that's why we had very little exposure to it. Now it's evolved, uh, so that everyone, even uh early training can get exposure. And the powers that be, so it was primarily Mike Jewitt, Neil Fleischer, Alex Alata at the time, decided to carve out a half day of our usual endoscopy time. Uh, so for those who don't know, we do all of our cystoscopies, um, in one unit, and it's part of EO. So down the hall they're doing Bronx, um, colonoscopies, etc. So we do only scopes in that time in that period. We can do consults, but it's not like a regular clinic where you can throw in a flexi here and there. So, Um, we made a, a concerted decision that we want this program, uh, identified when the radiation oncologists are actually available because that's also a challenge, uh, and we want them to have buy in and come in. Uh, so back then it was Mary Gospiderovich. She was a, a proponent of radiation for bladder cancer. So we had willing partners and then just carved out a half day. It's, and it's not a lot of patients. Uh, it's a half day on Wednesday. Uh, and our half day. Um, embarrassing as it may be, when it goes from 1 to 3:30 because everyone goes home at 3:30, um, is 9 or 10 patients. And so we started off very modestly because like how many patients are you're treating with primodal therapy? It wasn't a lot back in the day in 2008. So it is expanding, um, and wait time now is an issue, but we need to have players that had bought in, and we had that from radiation oncology and from uh urologic oncology. Uh, our compensation model is all basically based on the scoping and the radiation oncologist are paid by salary, so it doesn't matter where they are or where they're seeing patients. The one thing we would like to have is a medoc with us always. Um, we did have that for a period of time, but they, they come on occasion, but they are running a clinic. In the cancer center, which is across the street at the same time. So it's not hard to get access to them or just phone them up and say, we want to send someone to you. So that's how we run this multidisciplinary, uh, uh, clinic. It doesn't always have to be at the same time though. I've given talks on multi-D clinics, and I think it's just having people engaged and having the people interested, so you can always do things in series and not in parallel, uh, and not together, but it is easier to do it all at once. Yeah, from a biased standpoint like you talked about, I think that that has some value. I don't know if anyone else had any other questions as we're closing in on 8. Great talk. Thank you very much, Grish. Thank you, Chad. Published July 24, 2025 Created by
