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Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. Jason Efstathiou, a Professor of Radiation at Harvard, and the Director of the GU services in the Massachusetts General Hospital. Thank you so much for being here with me today. 

Jason Efstathiou: Oh, it's a pleasure. Thank you for having me. 

Alicia Morgans: Of course. So you have done lots of work over the last decade or so, probably more, on bladder sparing. And you were invited to speak at the EAU about the progress and the process that's involved with this. And I'd love to hear your take on bladder sparing, as someone with a really valuable perspective on that. 

Jason Efstathiou: Sure. I think you're right. It's a tipping point, I think, for what we would call trimodality therapy, the combination of some surgery, limited surgery, chemotherapy, and radiation. I mean, as we know, organ preservation has become commonplace in contemporary oncology. And while many patients do well with a radical cystectomy, it can be a physiologically challenging surgery and with potential real morbidity. This is well described in terms of long hospitalizations, high risk of reoperation, the long-term sequelae and even post-operative mortality.

The other thing that we know is that radical cystectomy, at least in the United States, is not being performed in over 50% of patients, or about 50% of patients that have muscle invasive bladder cancer. And so there's a gap that needs to be filled and I think trimodality therapy's perfectly positioned to fill that gap. 

The other thing is that it's important to remember that trimodality therapy, as I already alluded to, is a surgical approach. Very fundamental and important components of its success are the transurethral resection of the bladder tumor and having that done maximally and ideally visibly completely. And in addition, for the 10 to 15% of patients who need it, the back-up of a salvage cystectomy. Again, critical to the success of this approach. 

So when we see that paradigm being utilized and if we are able to sort of case match patients, long term results of trimodality therapy are actually very good and comparable, seemingly comparable, to radical cystectomy. As you know, we don't have the luxury of a randomized trial comparing these two different treatment approaches. But the best available prospective data would suggest that again, in case match patients, these can be equally good treatment approaches. 

The other things that I think are important in trimodality therapy that has evolved over the years are the importance of concurrent chemotherapy. That's been proven in large randomized trials that you need to add chemotherapy to radiation. The great thing is that there are many active radio-sensitizing drugs that can be used. And while cisplatin has been at the backbone of that, there are plenty of options for patients that are non-cisplatin candidates as well. 

Alicia Morgans: So, you know, I think it's great actually that trimodality therapy has actually been incorporated into guidelines. And like you said, I think a lot of that has to do with the fact that we have characterized methods to do this with different chemotherapy combinations, some cisplatin-based and then we have the 5-FU mitomycin combination for patients who are not cisplatin candidates and some others actually. But I think from a patient perspective this is something that they certainly ask me about. And because it's in the guidelines and because, actually, we worked together a long time ago, I feel quite comfortable with this approach. The one other caveat that comes up though sometimes with colleagues is who are these patients and what makes the ideal patient for a bladder-sparing or trimodality approach?

Jason Efstathiou: Yeah, great question. And just to take off regarding on that trimodality therapy is supported by numerous guidelines. Recently in the new addition of the NCCN guidelines for Stage 2 and Stage 3a muscle invasive bladder cancer, trimodality therapy with chemoradiation is a category one recommendation. That's a new change. That's listing it ... I mean the other category one recommendation, as you know, is neoadjuvant chemotherapy with radical cystectomy. 

So, coming back to your question on which patients are best for trimodality therapy, well I think it's Stage 2, Stage 3 patients. Historically, the best results are certainly found in those that have unifocal tumors, maybe under five or six centimeters in size, ideally have had a maximal visibly complete TURBT, that there isn't extensive or diffuse CIS, that there isn't hydronephrosis, and that the bladder works okay. But in a sense, the bladder is worth sparing.

Alicia Morgans: Yes. 

Jason Efstathiou: That urinary bladder function is acceptable and worth preserving. And certainly, also radiation is not great in patients that have underlying bowel issues, in particular, inflammatory bowel conditions. So I think a combination of what I just described probably would be the ideal candidate for bladder preservation. I think we're getting a little more liberal in that. There's a new trial that we could discuss as well that's opening nationally in the United States through a number of them, all the cooperative groups actually, that is a little more permissive and pragmatic. It allows patients, for example with unilateral hydronephrosis. 

So I think that the eligibility is expanding with time, but I think I'd probably hit on the main selection factors. Yeah.

Alicia Morgans: Absolutely. And I'm excited about that trial for many reasons, but one of them is that I've been fortunate to work with a group looking at quality of life. So we'll have a longitudinal quality of life assessment built into that trial to really understand what people are going through. From your experience with all of the protocols that you've done, what is life like after, for patients, after going through this pretty intensive therapy?

Jason Efstathiou: Yeah, great question. The reason to do bladder preservation is to keep the native bladder of the patient, but with the presumption that quality of life is better. And so if you look at the large trials that have been done in the US and in the UK, for example, grade three or higher GU, pelvic GU or GI toxicity rates, are well under 10% in the long term. So that seems to be acceptable toxicity. There isn't much quality of life studies that have been done and I'm glad we're going to be studying them prospectively within trials. 

But we did partner, the Mass General Hospital partnered with UNC to run a long term quality of life study in long term survivors of either cystectomy or trimodality therapy. And what came out in that, and I think that this is a consistent finding, is that there is markedly better sexual function in patients that go through chemoradiation compared to surgery. It sort of makes sense, but that one stands out. There was also a better sense of informed decision making. There was less life interference from cancer or cancer treatment. And there was less concern about appearance. Those were the main highlight points that I would say that were in favor of trimodality therapy in terms of quality of life.

Alicia Morgans: Those are pretty important things. 

Jason Efstathiou: Very important. 

Alicia Morgans: So I'm glad that you've done that work and I'm glad that we're continuing to study going forward. You know, as we move forward though in this field and you characterized who these patients are, it would be nice for all of us to not only use clinical characterization but to start to have a better understanding of the molecular drivers of who may be a better candidate for this treatment or that treatment. 

What is your team doing to really characterize the molecular heterogeneity, to identify those patients?

Jason Efstathiou: Great question. I think is certainly the frontier. Ideally, we want biomarker-driven management of muscle invasive bladder cancer. And ideally, those are predictive biomarkers that can predict which treatment a patient would do better with. So certainly there are going to be some patients that are better served by a radical cystectomy, somewhere they really need to add the neoadjuvant chemo to that. And there's data emerging in that space, as you know. 

But maybe there are some patients that are better served by trimodality therapy. We recently published in European Urology a paper that looked at immune and stromal infiltration. In the case of immune infiltration, patients that had high levels of immune infiltration, they seem to do better with sort of a trimodality approach compared to a surgical approach. That wasn't a perfect study, it was retrospective, and we need to study and validate these sorts of things in prospective large randomized trials. 

And that brings us back to what we were talking about earlier. I mean in the bladder sparing space, generally speaking at least in the US, they've been a series of smaller studies, often under 100 patients. But recently, SWOG and NRG, along with the other cooperative groups including ECOG and Alliance, are opening a large randomized Phase 3 trial of chemoradiation plus/minus atezolizumab. We all well know that there's a big role for immunotherapy, especially in advanced bladder cancer, and so now we're bringing it to an earlier stage, localized disease, and seeing whether the addition provides further enhancement of this therapy with hopefully better outcomes. 

So within that study is embedded, as you know, great quality of life work perspective, great biomarker work, and hopefully these will allow sort of platforms both for discovery but also validation because we desperately need that.

Alicia Morgans: I agree. I also appreciate that that study, to some extent, was a collaboration amongst all of these cooperative groups and defined, again to some extent. There's not hard and fast rules on all of this, but to some extent what are some standards of care, of delivering trimodality therapy. Because as people in the community I sure know if they try to start up a program for bladder sparing, there are multiple radiation approaches, multiple chemotherapy combinations or single agents that one can use. There are different ways of doing this and it's not that any of them have been compared head to head and really deemed better or worse, other than of course you know the 5-FU mitomycin I think is really the standard for patients who are not cisplatin eligible. 

But I really take some comfort knowing that all of the experts, or many of the experts in the field, got together and at least said, "This is a reasonable approach, we're going to standardize it in this protocol and do a large Phase 3 to kind of iron out some of the differences." Which, for better or worse, I think at least gives a road map for people trying to do these programs. 

Jason Efstathiou: You're absolutely right. And while the trial was called SWOG NRG 1806, it was very much an intergroup effort with all four cooperative groups heavily involved. And it allowed for all the investigators to get together and say, "Let's be pragmatic about this. How can bladder preservation chemoradiation be adopted by the broader community?" It's a 475 patient randomized trial. That would be, if successfully accrued to, the largest bladder sparing trial ever performed anywhere. Right? So it required that partnership but it also required laying out, as you say, the fundamentals of how do you do this treatment? 

I'm a radiation oncologist and I can tell you there're many in my field who aren't comfortable. I mean they want to do bladder-preserving therapy rather than cystectomy in the right patient, but they have never done it before and they needed kind of the guideline of how to do that. And I think this protocol really has done that. And along with being pragmatic, it allows different radiation field designs because as you say, one hasn't been proven better than another. You treat some of the pelvic nodes or not, you just focus on the bladder tumor or you treat the whole bladder. It's very permissive, it allows any of those approaches because they're all reasonable. It allows three different concurrent chemotherapy regimens. There's certainly, again, the backbone historically has been cisplatin, so that's one of them. There's 5-FU mitomycin-C, and there's low dose gemcitabine, which recently came out in a paper from an NRG RTOG trial in JCO showing that q day radiation, daily radiation, with low dose gemcitabine was a very reasonable approach and performed just as well as cisplatin or 5-FU. 

So, it allows any of those three concurrent chemotherapy regimens and it encourages also our urologic colleagues, do the TURBT twice. So if you're seeing a patient that may have been referred from another center, you should still do another TUR at your local institution so it's visualized and ideally maximally resected prior to initiating this. Because as we discussed earlier, that leads to better outcomes. 

Alicia Morgans: Yeah. 

Jason Efstathiou: So, I think on every front, the surgical, the medical oncology, and the radiation oncology, this protocol provides a really nice guideline of how to do this treatment. 

Alicia Morgans: Yeah. And with such a large trial and one that will be implemented within academic centers and in some community centers that really want to get engaged if they're part of these cooperative groups. 

Jason Efstathiou: Yeah. 

Alicia Morgans: I think this will be very, very helpful for us in the field. 

Jason Efstathiou: You're right. And without all of the community participating in this-

Alicia Morgans: It would never happen.

Jason Efstathiou: It wouldn't be successful. 

Alicia Morgans: No. 

Jason Efstathiou: Right? It wouldn't be feasible. So I think you're absolutely right about that. 

Alicia Morgans: Great. Well, any closing thoughts or final words for the listeners on this trimodality approach that you and your team have really pioneered over the last decade?

Jason Efstathiou: Yeah. I think, you know, it appears that now in 2019 patients with muscle invasive bladder cancer should be offered trimodality therapy and it should be discussed for a variety of reasons. Right? One, in contemporary series, survival looks good and comparable in match patients to cystectomy. Two, more than 85% of patients that are eligible for this approach maintain their native bladders. And generally, that's going to lead to favorable quality of life, as we discussed. Three, the guidelines are supporting this. 

Alicia Morgans: Yeah. 

Jason Efstathiou: As we discussed. It's even a category one recommendation for Stage 2 and 3a disease. Yes, the future is exciting. We're going to optimize concurrent therapies. Maybe that's going to include immunotherapy. We're going to look for biomarkers that can be predicted. Most importantly though, and perhaps my parting thought, is that multidisciplinary engagement is key here. Patients with muscle invasive disease who may be diagnosed by their urologic surgeon should meet with a medical oncologist and should meet with a radiation oncologist. And they should have a value of neoadjuvant chemotherapy discussed and they should have the option of trimodality therapy discussed and whether or not they are a candidate for such an approach. Because ultimately we need to safeguard the autonomy of bladder cancer patients and we have to really encourage patient directed informed decision making. And I think that's key. 

Alicia Morgans: I could not agree more. Thank you so much for taking the time to share your perspectives and expertise. I really appreciate it.

Jason Efstathiou: Thank you very much.