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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, and work at Vanderbilt University Medical Center. And it is really an honor and a privilege and excitement to have Dr. Doug Dahl from the Mass General Brigham Department of Urology in Boston, Massachusetts. I've actually known Doug since our college days together, and our paths have crossed many times. And what he has been able to accomplish surgically and clinically with his wealth of experience and outcomes have really actually impacted patient care for many, many years.

Doug and his team have actually put together a series looking at trimodal therapy or multimodal therapy—a combination of chemotherapy and radiation—for patients with non-muscle-invasive bladder cancer with T1 disease, actually specifically. And this article was recently published in the Journal of Clinical Oncology. So we're very fortunate to have Doug present his work and look forward to asking him a few questions. So Doug, thanks again.

Douglas Dahl: Well, Sam, it's a great privilege to be here with you tonight. And it's been a marvelous part of my career to be able to see you so often professionally, and our paths cross personally too, as well, which has been terrific. So—

Sam Chang: Absolutely.

Douglas Dahl: Thanks for inviting me tonight. Tonight, we're going to present results of our Phase II trial of trimodality therapy for T1 high-grade bladder cancer, a very specific niche. And why did we study this? Well, trimodality means chemotherapy and radiation, but it also means surgery. It means transurethral resection of bladder tumors. And so it's been an amazing privilege for me to work at Mass General Hospital for 23-plus years, where we've had a long history of exploration and validation of this option for patients with muscle-invasive bladder cancer as an alternative to radical cystectomy.

There is this niche of patients where they have technically superficial cancer but they have failed intravesical therapy. And really, the clinicians are faced with a difficult question of do you try new other things, or clearly we're worried about them having occult more aggressive disease, and radical cystectomy is often recommended. So this was our trial, looking at trimodality therapy—first-time proof of principle in this specific niche of patients with T1 high-grade who have had BCG and are facing cystectomy, who have not been cured with BCG.

Now, trimodality therapy, as I mentioned, has had a long history of proven efficacy. It remains controversial, and I think it comes off often among the urology community as that, oh, you just don't know how to do a cystectomy. But the reality is there are a lot of patients who are not good candidates for cystectomy. There are a lot of other examples in evolution of surgical oncology where we've shown that less aggressive, less disfiguring surgery can have a place. I think of laryngeal cancer, where it's so rare for us to see a patient walking around having had a laryngectomy. Anal cancer, where patients have had to have a complete anterior-posterior resection.

Thankfully, those are fewer and fewer cases, and I would argue that we need to embrace the role that trimodality therapy does have in bladder cancer. It does not mean radical cystectomy is not a superb option for many patients, but this particular niche of patients is really difficult. So per the NCCN guidelines, if there's T1 disease, despite BCG therapy, radical cystectomy is preferred or strongly considered. Everyone knows that when you face these patients, it's important to let them know that there can be occult more serious disease.

And we looked at an important retrospective study from Europe, which was patients not who had had BCG but had a grade 3 T1 disease, who went on to immediate cystectomy. And there were 1,136 patients in this cohort. And you can see in figure A, this was their recurrence rate over time—many, many years—but a high recurrence rate. More than a third of the patients did have recurrence, and almost 40% of the patients ended up dying of urothelial cancer despite radical cystectomy for a grade 3 T1 disease. With the success of trimodality therapy in proven muscle-invasive disease, we developed this study to look at patients who had been recommended to have a cystectomy. So their alternative was radical cystectomy or trimodality therapy.

So we—part of this is important is the transurethral resection and the expertise of the surgeons to make sure that visibly complete resection of all bladder tumor is possible. They then got radiosensitizing chemotherapy, and I think that's not something widely understood. It's a lower dose. It really is given with the radiation, potentiates the effect of radiation. So it's not really systemic curative-level chemotherapy. Most patients did receive a cisplatin-based regimen. Some couldn't tolerate cisplatin, got mitomycin and 5-FU. We did have regular cystoscopic evaluation routine in the office.

This was not specified. This was a multi-center NRG RTOG national trial. So there were some individual variations in whether this was in the operating room or in the office. Our primary endpoint was bladder-intact survival—how many of these patients went through this program did not require cystectomy. Secondary endpoints we looked at were overall survival, disease-specific survival, and we wanted to get a sense of the morbidity and the quality-of-life impact of this versus cystectomy. So we ended up enrolling 34 patients. It turns out it's a pretty specific niche of patients to try to find this group that still has not responded to BCG or cystectomy is clearly the next step for them.

They underwent trimodality therapy, and exceeding our expectations, 88% of the patients retained their bladder. The four patients who underwent cystectomy, very interestingly, there was no muscle-invasive disease found in any of them. So they had undergone cystectomy for—worried patients—the clinicians were worried that they may have more aggressive disease. They had significant CIS. There was one patient who had a really poorly functioning bladder. So there were a couple of different reasons why people had cystectomy, but the vast majority of the patients had a bladder intact.

Overall, disease-specific survival was 75%. Recurrence rate was seen in a third of patients. So when you look back at those graphs originally of the patients who underwent de novo cystectomy at the first diagnosis of grade 3 T1, unfortunately you still see that there is in our group, there was 25% of patients who ended up dying of urothelial carcinoma, which is lower than in their group, actually. And because we're retaining the bladder, we do see recurrence, and many of these were local recurrences of the bladder.

So the landscape of non-muscle-invasive bladder cancer is changing. Dr. Chang has been very involved in developing some of the treatments for these really difficult patients that continue to fail intravesical therapies. But you don't really want to have to take the next step to doing a radical cystectomy. Even with all those developments, I think this paper is important in that it's going to give a window into the possibility of even patients who failed some of these novel treatments. Unfortunately, that's going to happen. Is this an alternative to considering cystectomy in these patients?

We still have to weigh the risks and benefits of cystectomy with these patients. Metastatic disease remains a very common, challenging problem despite good local bladder control. And we see that every day in managing bladder cancer, unfortunately. And patients can be cured locally, yet show up with metastatic disease, which remains one of the really difficult things about urothelial carcinoma. So this, we think, suggests a reasonable alternative to cystectomy in the patients who are facing the failure of intravesical therapy, whose next step is cystectomy. And clearly, we need to do more work in improving systemic therapy. Thanks for inviting me tonight to discuss this work.

Sam Chang: Doug, fantastic. Obviously, very important work. I think we have developed over the past few years a new important kind of endpoint, which is that cystectomy-free survival rate—that ability to avoid cystectomy—that's really evolved over the past few years. Ten years ago, you've never heard that; maybe even five years ago would have been very uncommon. But clearly, from a patient standpoint, it's really become an issue that is paramount of like, what are my options? What else are there to do?

And formerly urologists, we were just a hammer and the nail was to get that thing out of there. But I think there is a better understanding of multiple possibilities—intravesical, and now radiation combined with chemotherapy. Tell me first, how did patients do symptomatically from this? Because a lot of these patients have had lots of intravesical therapies, have had CIS, T1, etc. So tell me about the symptoms and side effect profile.

Douglas Dahl: Well, it is remarkably good. Now, we've all seen patients that had pelvic radiation therapy and they have very poorly functioning bladders. This group was a fairly small group of patients, but their AUA symptom score index did not change on average very much. And we have—my colleagues and I at Mass General have done papers looking at urodynamic outcomes after trimodality therapy. Most patients actually retain a good-quality, high-volume functioning bladder and have good quality of life. So it is, I think, a testament to good relationships among multidisciplinary groups to coordinate the chemo and the radiation and the cystoscopic evaluation. And some places have had real struggles with patients having toxicity from the bladder, from not really having good coordination of those things.

Sam Chang: I think that's appropriate. If someone has a small capacity, lots and lots of lower urinary tract symptoms, that's not—you're not doing anybody a favor if somebody's bladder capacity is 120 cc's, multiple issues already. Tell me about—I know on protocol, but say now we're past the study kind of regimen. Tell me kind of the surveillance for these patients. Is it every few months, and we space it out just like we do with other non-muscle-invasive bladder cancer cases? Do you always do biopsies? Do you do cytology? Tell me a little about the surveillance for these patients.

Douglas Dahl: So initially we were very rigorous about having to take them to the OR to biopsy them. Over time and with experience, we've learned that really your visual cues, like in regular patients, are very good. So less and less are we feeling the need to take deeper biopsies of things that look superficially normal. So for the most part, patients go back to being pretty typical surveillance patients of superficial bladder cancer.

Sam Chang: OK, fantastic. And then those that do have recurrences, because 25%, 30%—I guess a third had some disease recurrence, some outside the bladder, some inside the bladder. So two questions: let's focus in the bladder. Do you treat those with intravesical therapies? Is that usually the standard treatment?

Douglas Dahl: Yeah, it's interesting. Not just in this study, but our overall experience is that you basically treat them like you would as if they were their first presentation—resection. And intravesical therapy still is effective. Particularly CIS doesn't tend to respond to the trimodality therapy, does respond to BCG even after radiotherapy.

Sam Chang: That's great. So then this leads to my next possibly provocative question because I don't know the answer to this. So with the field of radiation that was used for these patients, were the pelvic lymph nodes covered with this or was it just bladder-centric? Because I'm trying to see if there's perhaps some way—obviously, you add morbidity, but perhaps you decrease that likelihood of either recurrence or go ahead and help sterilize the field that may have micrometastatic disease with a bigger field. Tell me a little bit about the radiation field.

Douglas Dahl: Yeah, I think that's evolved a lot. Now, this study was conceived before we had more specific designations of BCG recurrent or BCG unresponsive. We did not allow some of the more modern radiation therapy techniques that are now in vogue. So it was really—there was some individual tailoring by the radiation oncologist in this group. I think pelvic—at the time, pelvic radiotherapy for nodes was not as common because the toxicity still was an issue. So it wasn't allowed. But I don't think that it was a common part of the overall treatment.

Sam Chang: Great. No, I mean, this is—to me—is very, very important because honestly, it's the first time that showed basically that this combination trimodal therapy with the aggressive resection with the treatments, with systemic therapy and then with radiation therapy—that the vast majority of patients actually can retain their bladders. If they develop disease in the bladder, most of the time—many times it can be controlled with intravesical treatment. But then the caveat being like with all these patients actually, that we don't proceed with surgery for BCG-unresponsive disease, you have to worry about the development of metastatic disease and micrometastatic disease. So tell me, Doug, is this now something that you regularly will discuss with bladder cancer patients with T1 disease that doesn't respond to BCG? Is that now on your list of treatment options?

Douglas Dahl: I think that yes, it should be. I think this is a challenging space, as you know better than anybody. The clinical judgment, as you mentioned—you have to be a urologist, you have to understand where people are starting their voiding function. I think that's a very important role for the urologists is to show clinical judgment of who could tolerate these things. Obviously, somebody's already severely suffering from lower urinary tract symptoms, they're not going to do well with this type of treatment.

I've spent a lot of time really poring through the studies of the more recent developments in how do you treat BCG-unresponsive disease or recurrent disease. And there's some amazing hopeful data there, but it's still pretty small numbers and pretty early. So I think that it's important to keep this option open. I think we have more work to do. There's a new trial that's a follow-on to this now with NRG.

Sam Chang: That's good to know.

Douglas Dahl: Yeah, so that's been approved and that should be enrolling. That does include immunotherapy as a component of the treatment. So refining, obviously, as we hope to do with every study. What have we learned? What do we need to—what didn't we understand or anticipate when the study started? And where do we go in the modern landscape of treatment? So it's an area that had very little progress for so long. And it's now really an exciting area. And some of the works with the transfection of the urothelium to express interferon-related—

Sam Chang: No, it is an area that was really a little bit of a desert. And now, I mean, there are multiple trials, multiple options. To your point, it has really become an area of very fertile research and obviously very exciting times for patients. And I think an important telling point to the audience is, of those few bladders that had to be removed, the fact that none of them had invasive disease. I mean, I think we worry about metastatic disease, but we obviously worry about either missing invasive disease or invasive disease developing.

And so it was, I think, quite telling that none of these patients had invasive disease. And I agree with you. I can tell you that there is no question that at our institution and I think nationally, that the choice for invasive disease—and now, we need to consider for T1 disease the possibility for select patients in the T1 population that this multimodality may really become a treatment that is part of the list of options that we have for our patients. Obviously the clinical trials, obviously cystectomy, immunotherapy, the new medications, etc. So I think it's a really exciting time.

And I just wanted to thank you and all your colleagues with the NRG study and what you all have done. But really the efforts that all the folks in Boston have done, looking at attempting bladder-preserving types of treatment—that really you all were a little bit of an island in the US for decades, and now people are realizing, obviously the groups in Germany have been quite influential, but really have led the way. So thank you, and we all applaud you and we look forward to future studies. And most importantly, thank you for being a great friend and appreciate always your insight.

Douglas Dahl: Well, it's a great privilege and a pleasure to be with you this evening. And thanks for allowing me to spend some time discussing our work.