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Sam Chang: Hello, my name is Sam Chang. I'm a Urologist in Nashville, Tennessee, and I work at Vanderbilt University. We are lucky to be joined today by Dr. Sophia Kamran. Dr. Kamran is an Assistant Professor of Radiation Oncology at Massachusetts General Hospital associated with the Harvard System in Boston. She and I are enjoying some wonderful weather here in San Francisco at the GU ASCO meeting. But I'm fortunate to be moderating a session where she is going to be presenting actually highlights and updates on trimodality therapy for bladder cancer. So I had asked Dr. Kamran to give us highlights of her presentation and I've been lucky enough to see it. And I've learned quite a bit. So, Dr. Kamran, I'll leave it up to you to start.

Sophia Kamran: Okay, great. It's a pleasure to be here. Thank you so much. So, as we all know, trimodality therapy is an excellent treatment option for patients with muscle-invasive bladder cancer. And so there has been a lot of novelty with trimodality therapy. It's been adapting a lot. And so basically one of the things that we are going to be talking about and that we are interested in is how to improve upon outcomes even further in TMT and specifically, how do we combine some novel therapies with radiation therapy to have better outcomes for patients with muscle-invasive bladder cancer.  One area that is very hot right now is immunotherapy. So immunotherapy has been shown to be very effective in bladder cancer, urothelial carcinoma. So we want to know, can we improve on outcomes with TMT by you incorporating immunotherapy?

So that is one big area that I'll be just discussing lots of different updates. We know that in other disease sites radiation and immunotherapy work synergistically to really improve upon each other in terms of overall outcomes. So we are really hopeful that by incorporating immunotherapy with TMT, we can also see those gains in survival, disease-specific survival, things like that. So there's a big, big trial that is going on right now, the NRG/SWOG 1806 (S1806) trial that I will be discussing is actually randomizing patients with muscle-invasive bladder cancer to either standard trimodality therapy or the standard therapy plus atezolizumab.

Sam Chang: So it would be standard chemotherapy.

Sophia Kamran: Oh, standard chemoradiation therapy.

Sam Chang: Chemo with radiation therapy.

Sophia Kamran: Yes.

Sam Chang: Versus that combination, but adding the immunotherapy as well.

Sophia Kamran: Exactly. Exactly.

Sam Chang: Okay. Do you have any early signals or do we have any idea at this point?

Sophia Kamran: Well, one of the things that were presented last year actually at the symposium was safety data. So that is one of the big questions, is it safe to combine immunotherapy with radiation therapy? And so thankfully we do have that early data. It was in 73 patients and it is thankfully very, very safe. That was definitely a big question.

Sam Chang: What were their concerns? Was it just the toxicity profile or the inability to continue the radiation? What were the concerns?

Sophia Kamran: Pelvic toxicity, GI toxicity specifically. And one of the reasons why is actually, so hypofractionated radiation therapy is actually another hot topic in radiation oncology for bladder cancer. So there has been a lot, basically what hypofractionated radiation therapy means is that we're giving a larger dose per day, so we can actually shorten the duration of the overall treatment. However, in combination with immunotherapy, it does appear at least at this time with very early trials, just in a few patients that there does seem to be an increase in toxicity, specifically GI toxicity. There are ongoing trials with hypofractionated radiation in combination with different immunotherapies and we are going to have to wait for that data, but it was very surprising to see that there was quite a bit of GI toxicity, where actually those trials were stopped.

So with the NRG/SWOG 1806 trial, right now, it's just conventional fractionation, we're not using hypofractionated radiation therapy because I think more work needs to be done in that area to understand the safety and the toxicity profile.

Sam Chang: So for patients, give us a general idea of what a standard length of treatment would be for conventional timing of radiation therapy versus the hypofractionated course. Are we talking months difference, or just a few weeks?

Sophia Kamran: It's usually 36 treatments is the standard versus 20 or 25 treatments. So yeah, there is.

Sam Chang: Oh, a substantial difference.

Sophia Kamran: Yeah, so there is a difference.

Sam Chang: So would you have guessed that this GI toxicity would come about or was this a big surprise to many of the radiation oncology folks?

Sophia Kamran: I think it was a little bit of a surprise and especially because in those trials they actually try to lower the dose of the immunotherapy yet it still had to be stopped. It was still deemed to be too toxic. So patients could not get through it. So I think it was a little bit of a surprise, but also we do know that immunotherapy, and because they do work in combination with radiation, maybe we shouldn't have been so surprised because, we do know that it is a very powerful combination, so we need to understand.

Sam Chang: [crosstalk] inflammation, colitis.

Sophia Kamran: Yes, exactly, exactly.

Sam Chang: And so this combination then, given either with atezolizumab or without, the thought process would be, there might be an increase in toxicity, but the trade-off perhaps would be differences in disease-free survival, recurrence-free survival, et cetera.

Sophia Kamran: Yes, exactly.

Sam Chang: And how is that trial accruing?

Sophia Kamran: It's doing very, very well. Yes, it's accruing very, very well. So the total is expected to be 475 patients. And I think as of right now, we have over 200 patients accrued, so.

Sam Chang: I think, I mean, I think urologists, we fall way behind in a lot, a lot of areas, but we definitely fall behind in terms of the radiation oncologists as well as the medical oncology colleagues, in terms of enrollment in trials and one of the things that we as a group need to do is a better job in terms of enrollment and offering our patients these trials as well.

Sophia Kamran: Yeah.

Sam Chang: So what other highlights from your talks?

Sophia Kamran: So another thing that I highlight is adaptive radiation therapy. So adaptive radiation planning is coming down the pipeline. It's a very, very novel treatment, basically what, and we think bladder cancer is a perfect disease site to really treat with this. So basically what it is, is that we adapt the radiation plan on a daily basis. So each day, based on the anatomy on that day, we can actually adapt the radiation plan and the thought is that because obviously there are daily changes every single day, if you're undergoing like 36 treatments or even 20 treatments, things like that. So the thought is that if you are actually adapting to what things look like that day, we can actually further spare normal bowel, the rectum, things like that, things that obviously do cause toxic side effects. And we can really dose escalate to the area where the bladder tumor was or the bladder itself. And so that's another thing that is kind of coming down the pipeline and that might be actually an area where we can, with the combination of immunotherapy, maybe adaptive radiation plus immunotherapy in that context, maybe that's where we can do the hypofractionation.

Sam Chang: And then decrease the possible toxicity with it.

Sophia Kamran: Yes, exactly.

Sam Chang: And have you individually, have you started some of the adaptive, have you yourself or your team started those types of things?

Sophia Kamran: We're actually getting the new machine, I think it's going to be up and running in a few weeks.

Sam Chang: So, it's a machine and I guess, software-related as well.

Sophia Kamran: Exactly. Yes, yeah.

Sam Chang: I see, okay.

And does it, how much longer per day, one of the big advantages of radiation therapy is the treatments are so short usually during that day, they drive in many times, it takes longer to park and register than the actual treatment. How much time does it add additionally to a patient's, I guess you don't know, you haven't done it yet.

Sophia Kamran: That's a good question.  No, but other centers that do have it do add some treatment time, but again, I think it depends on how.  It's a team-based approach and how up to speed, how quickly you can adapt the contours. I think if there are drastic changes, that is obviously going to take a little bit longer to do that quick adaptive plan. If it's just a tiny change each day and you can use yesterday's anatomy and kind of apply it to today and there are no big changes, I think it could be no.  I mean, it's still going to be a little bit more, but I think it wouldn't be too dramatic, but we will find out more.

Sam Chang: Yeah, as a patient, you would think, boy, this sounds like an absolute best possible idea.  Just as we treat our prostate cancer patients, we now, many times get multiparametric MRIs.

Sophia Kamran: Yes.

Sam Chang: Why the visualization is so much better, an idea of what we can do in terms of nerve-sparing.  It seems to make the most sense of as opposed to radiating that table, that is not moving. We know the bladder is changing all the time, the configurations, bowel gas, all those things. That is wonderful, any other highlights from that?

Sophia Kamran: Yeah, so I think another area that you know is, again, where our field is going, where the field of radiation oncology is going for bladder cancer patients is really involving and incorporating the use of biomarkers. So, my lab has been doing a lot of work. Our team at MGH has been doing a lot of work on biomarkers to understand, who benefits, who doesn't, who has toxicities, who does not have toxicities, where is the level on a patient individualized level, where can we find that benefit, who deserves dose-escalation, who doesn't need it necessarily? I think that's kind of the area we need to go to. And that can also help us with adding on immunotherapy versus not adding on immunotherapy. Maybe some patients, their tumor microenvironment tells us they would dramatically benefit from immunotherapy versus others. So I think that is another area of need. We're going to get lots of great information from the SWOG NRG trial because we are collecting all sorts of tissue and urine specimens, all sorts of biospecimens. So we are going to be doing a lot of translational work, so it's very exciting.

Sam Chang: Do we have any early signals of what those biomarkers may be with radiation? I mean, we have, we are learning, obviously that we've got targets, molecularly based targets for some of our medical oncology interventions in terms of we've got, oh, BRCA2 mutation, we can use this type of event. We can use PARP inhibitors in our field with upper tract disease, FGFR3 mutations for either bladder cancer or upper tract disease. We've got a target now. Do we have any signal of tumors, at least from a molecular level that may be more radiosensitive than not?

Sophia Kamran: Yeah. So, that's a great question. So nothing definitive yet. It's all very early data, but in general, we do see that when patients that have DDR mutations, there may be a signal where they are more radiosensitive, and then there has been some other work where we look at RNA signatures, you could look at these signatures and it appears that there are certain signatures that actually may tell us that these tumors might be more prone to responding to immunotherapy versus not. So, it's extremely early data, but I think we need to do the research to really solidify what these biomarkers are.

Sam Chang: So as a urologic surgeon that sometimes performs cystectomies, should I counsel all my patients that they should at least consider trimodal therapy? And I can tell you that honestly, probably 10 or 15 years ago, I really rarely, honestly counseled them to consider discussions with radiation oncologists. I think that has dramatically shifted. Have you, you're at the Mecca of, in all honesty, bladder sparing preservation therapy, it's a world center of excellence for sure. But have you noticed within the country that there has been a shift to at least understand and incorporate bladder sparing treatment options for our patients?

Sophia Kamran: Yes. Definitely. There's definitely been a big paradigm shift. I think people are recognizing that we don't have any head direct comparisons and we probably never will, but from all the data that we do have where we can best, compared to radical cystectomy series, it shows that it's just as good with modern TMT, it's just as good as modern cystectomy series outcomes. We know functionally, patients do really well, so, that's one of the concerns, but I think people are understanding that we have the data showing that patients do well from a functional standpoint and from a quality of life standpoint, and from a toxicity standpoint.  People are always also worried about two years of pelvic toxicity after radiating, et cetera, et cetera, but people actually do extremely well. So I do feel like, especially with the SWOG NRG trial, because again with trimodality therapy, it's called trimodality because we do incorporate the use of, urology plays a huge role and I think that urologists all over the country are recognizing that.

Sam Chang: I think so too, in understanding that we need to at least educate our patients regarding the options.

Sophia Kamran: Yes.

Sam Chang: There are pros and cons to every treatment that we choose, and understanding that there are trial options available. Because many of our patients are interested in trials. So I think it's with, especially with, advanced treatments and now with better, hopefully like you said, individualized or personalized care if we can actually incorporate some of the biomarkers you're talking about, find out what they are, I think it's a huge, huge move forward. So, Dr. Kamran, thank you so much for spending some time with us.

Sophia Kamran: Absolutely.

Sam Chang: And I look very forward to your presentation coming up at GU ASCO.

Sophia Kamran: Thank you for having me.

Sam Chang: Absolutely. Thanks again.