Sam Chang: Hello, everyone. I am fortunate to have today, Dr. Deborah Kaye joining from Duke University. She is an Assistant Professor in Urology there at Duke, and I've known her ever since her days as a resident at Hopkins and her fellowship at University of Michigan. She was chosen this year to be the discussant at GU ASCO 2022 to focus on the best papers with discussing urothelial carcinoma. And so we've asked Dr. Kaye to give us the highlights of the presentation that she'll be giving. My name's Sam Chang. I'm a urologist in Nashville and I work at Vanderbilt. So Dr. Kay, Deb, can I call you Deb?

Deborah Kaye: Sounds good.

Sam Chang: Thank you so much for joining us. And I just want you to give us kind of highlights important to you of these four different papers that I think you've decided to highlight.

Deborah Kaye: Yeah. Thank you. And thanks so much for having me here. So I reviewed a lot of papers and there was a lot of good literature that came out the past year. I chose these articles specifically given their clinical relevance and how they have direct impact on patients today. So the first paper that I chose was adjuvant nivolumab for high risk muscle invasive bladder cancer patients after radical cystectomy. And the paper basically found that in patients with high risk of recurrence, that adjuvant nivolumab improved disease free survival, and it was about 20.8 months compared to 10.8 months.

Sam Chang: So a doubling-

Deborah Kaye: Yep.

Sam Chang: ... of an adjuvant therapy actually post cystectomy, really something that we've struggled with for quite some time of do we give something, do we not? Really a significant difference.

Deborah Kaye: Yeah. And the important part is they included patients that did or did not have neoadjuvant chemotherapy. And there is some question in the article as whether there was maybe greater impact for patients who had neoadjuvant chemotherapy or where that's really where the improvement in disease free survival was found. The cohorts in those subgroups though, most of those still the hazard ratio was less than one. And the study was really powered for the overall cohort.

Sam Chang: So I guess in addition in that study, I think almost 20% also had upper tract disease. So perhaps led some credence that even considering it for upper tract after nephroureterectomy to consider adjuvant immunotherapy. Is that correct?

Deborah Kaye: Yeah. They capped the study at 20% because they didn't want too much upper tract in their study. The hazard ratio wasn't quite as significant for that. So they're still not sure. But the overall cohort where those patients were included, it does suggest a disease free survival benefit.

Sam Chang: So how is this study going to affect your practice? Because I know you have a very busy clinical practice at Duke. Is this something that really, at this point, you would consider then counseling all your patients of that have high risk features following radical cystectomy?

Deborah Kaye: Currently, I have changed my practice pattern based on this paper. For patients who are high risk of recurrence, and basically that's any patient that has node positive disease whether or not they've had cisplatin based chemotherapy. If they did have cisplatin based chemotherapy and they were CPT3 or T4A, or did not have it and were PT2 to PT4A, I do discuss this with them. And I discuss the pros and con and I will refer them to medical oncology for further discussion.

Sam Chang: Yeah, I think definitely significant findings found in that study. How about the next study, next paper?

Deborah Kaye: So the next paper is pembrolizumab monotherapy for BCG unresponsive non muscle invasive bladder cancer. As we all know, this is a really difficult space to be in and a difficult space to practice in. And the study found that pembrolizumab as monotherapy does have some benefit in terms of recurrence-free survival and disease specific survival.

Sam Chang: So with pembrolizumab, do you think that all our patients now that have BCG unresponsive disease, should we now then call in our medical oncology colleagues to at least discuss using pembrolizumab? Or are you trying to alter your practice based upon clinical trials that are available? Or do you try another [inaudible 00:04:42] therapy? Where does pembrolizumab fit in your treatment paradigm?

Deborah Kaye: So for these patients, it really was for patients who they refused a cystectomy or they weren't a candidate. So I think that's really where this fits in. You know, I still think that a cystectomy is the standard of care for BCG unresponsive patients. But for those patients who aren't going to make it through a cystectomy or who absolutely will not tolerate it.

Sam Chang: And there are definitely patients, unquestionably, that fit that category or that categorically refuse cystectomy, you're looking for options.

Deborah Kaye: For something.

Sam Chang: I think that's really, it changed things. I agree with you.

Deborah Kaye: This was about, it was about a 41% response rate, which is decent. And the response rate was pretty long lasting. It was still, the overall study cohort still had a short follow up. So it's still yet to be seen kind of how long are the really long responders, and that's going to be definitely something that we're going to need to look for the further data.

Sam Chang: Yeah. I think at least having that option for systemic therapy, understanding the caveat we've introduced possibly side effects associated with that systemic therapy. There's definitely some patients who respond and respond for a long period of time, just as you said. I think that, you know, should all patients be advised or counseled by our medical oncologist? I don't know in this space if that's the case, but it's definitely something that we need to discuss with our patients that there is now an FDA approved agent, even though it is systemic, for non muscle invasive disease. What about the third paper?

Deborah Kaye: Yeah. So the third paper was reduced dose BCG in the era of BCG shortages. And it was a single center study out of MD Anderson and really found that in their retrospective cohort of over 500 patients that decreasing the dose to one third dose versus full dose BCG, there was no difference in recurrence free survival time to progression and overall survival.

Sam Chang: Do practitioners in your group, or in the Raleigh Durham area, or in North Carolina, have you all continued to have BCG shortages?

Deborah Kaye: So we've been really fortunate at Duke. Our BCG shortages have been fairly limited. I do know that institutions in the area, that they've had some major problems with BCG shortages. And so I think this still continues to be a problem. And then I've also heard a lot of my patients in a more community setting that want to get, you know, because they don't want to travel a few hours to get their care at Duke, that they can't receive BCG-

Sam Chang: They cannot get BCG.

Deborah Kaye: ... in their local settings.

Sam Chang: So I don't know if you know this, do you have any inside information on the plant that's being built in Raleigh/ Durham? I know that, that's the site, it's supposed to be in the Raleigh/Durham area. I've seen designs. What kind of progress has been made? Do you have any idea?

Deborah Kaye: I've heard about it, I actually haven't, I don't know any specifics about it.

Sam Chang: Well that, in itself, I think, is something that we need to always consider, in that, even if this plant, that's going to be built to increase the production of BCG, this is years away.

Deborah Kaye: Yeah.

Sam Chang: So this issue of BCG shortage, is going to be around for, I think, for at least, for years. And understanding that you can stretch out the dose of BCG, at least in terms of the actual amount given, not necessarily the regimen, may be actually really important.

Deborah Kaye: Yeah.

Sam Chang: When you all do have a limited supply, what is your tendency? Do you tend to reduce the concentration? Do you tend to avoid maintenance? What are the strategies that you guys employ at Duke?

Deborah Kaye: So I think, each practitioner's a little bit different in how they do it, and their protocols. I tend to reduce dosages. I don't like to, I think maintenance therapy is extremely important. I think the data points towards that. So I do induction plus maintenance. And then, we also do other therapies such as, gem/doce, or other therapies. But I think it's, using this data, I think it's really important, to use it in obviously, well selected patients. I don't think, someone on their second dose of BCG induction therapy should receive one third dosage.

Sam Chang: Should automatically, right.

Deborah Kaye: But maybe someone with a solitary high grade tumor, this may be an option for, in cases where you can't provide full dose BCG.

Sam Chang: Right. And also, understanding that this was a single series, even though a big center like Anderson, and also, that it was retrospective.

Deborah Kaye: Yeah.

Sam Chang: So understanding that some of the patients may have been selected for certain reasons. We don't really know.

Deborah Kaye: For sure.

Sam Chang: But at the same time, it does give us an idea of the efficacy of BCG, may not be as dependent upon the concentration and the amount, but the continued scheduling that we provide.

Deborah Kaye: Yep.

Sam Chang: The Anderson folks have also looked at, how each vial can have a different amount of living organisms.

Deborah Kaye: Yep. Yep.

Sam Chang: And how they can be so automatically, one third actual dose may have just as many colony forming units-

Deborah Kaye: Yeah.

Sam Chang: ... as a full vial. So I think, the challenge of receiving the medication, like you were just saying, in a regimen that is continued, that includes maintenance, is actually really, really important.

Deborah Kaye: Yep.

Sam Chang: What about the fourth article?

Deborah Kaye: So the fourth article was, The Health Related Quality of Life for Patients Undergoing Radical Cystectomy. And that was also, it was a series out of Memorial Sloan Kettering, but this was a prospective study, where they took it where they did health related quality of life surveys before surgery, and a total of five time points. And they basically found that there was no difference in health related quality of life, amongst most measures that they captured, two years. Really, usually, between three to six months after cystectomy and up. And then, usually by two years, everything was better.

The important caveat. I mean, they did break things down by urinary diversion type. So ileal conduit versus, a catheterizable channel. And there were some differences. The main thing that they found, in terms of sexual function, didn't get quite back up to baseline, but it was poor to begin with. Mental health scores actually, did really well after surgery, actually improved beyond baseline. So the study was just, it's really interesting. And for me, it has direct ramifications. Because I have a lot of patients who, are just concerned about their health related quality of life. How they're going to function after surgery, whether it's with a neobladder, or an ileal conduit. And this can provide some data to show them, look, it sounds really bad, it sounds awful, but at the end of the day, hopefully, we'll get you cancer free, and your health related quality of life is hopefully, not going to be too bad.

Sam Chang: That leads to the question I was going to ask you. With this trial, how has it affected your counseling? Have you used that terminology specifically, in terms of, look, it's really not going to impact your life, once we get to a certain time point. Is there anything else that, from the study, that you use to help, in terms of counseling?

Deborah Kaye: It provides me with some data. Right? Because I think patients want to hear, they want to hear other people's experiences. Right? So counseling is a huge deal, and support networks are a big deal. But this provides patients with actual, something that they can read, and something that they can see the time course. Right? So at three months yeah, I may be struggling a little bit, or I may be having some of these issues. But really, by six months, hopefully, I'll be kind of back to baseline, maybe even above baseline. And then by two years, hopefully, things will be good again, in terms of my health related quality of life.

Sam Chang: And then, within that trial, were there differences between the diversion types?

Deborah Kaye: There were some differences. The main thing was, well, sexual function was bad in both groups. And then, the other thing is, body image was a little bit worse in the ileal conduit group. It wasn't terrible though, for sure. And the authors pointed out that, it's really important that we can't make comparison conclusions based on this study between the two different-

Sam Chang: Between the two types.

Deborah Kaye: ... diversion types two types. Because it, that's not how this study was designed. So yes, there are some differences, but I don't think you can say one is better than the other. And there were some difference in baseline function between the two cohorts.

Sam Chang: So as you counsel your patients, in terms of quality of life, is there anything from this paper then, that helps you, in terms of determining, you should have this type of diversion versus that? Not really. No, not.

Deborah Kaye: No. It really is, mine is really about how a patient functions at baseline, and their preferences. And we go, we have a pretty thorough discussion about what they want, and what they're willing to take, in order to get exactly what they want. So, the risks and benefits of the diversion types.

Sam Chang: How many articles did you look at?

Deborah Kaye: It was a lot.

Sam Chang: I don't even want to think about it.

Deborah Kaye: A lot articles.

Sam Chang: A lot of articles, yeah.

Deborah Kaye: I learned a ton.

Sam Chang: Yeah.

Deborah Kaye: But it's exciting, what's going on, in the world of urothelial cancer. Things are really changing, and I think that's, it's exciting. And it was really hard making these decisions, and just choosing four articles. But I had to limit it to something, and these were directly clinically relevant to my practice, so.

Sam Chang: Absolutely. Well Deb, thank you so much for spending some time with us. And I look forward to the discussion, because I know, that each of these papers will make a difference, in terms of a clinical practice. So, thanks again.

Deborah Kaye: Thank you.