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Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee. And I have the great pleasure of welcoming Dr. Jeff Holzbeierlein. Jeff and I go way back. We were actually residents together at Vanderbilt, and he currently is the Chair of Urology at Kansas University, at KU. And obviously a real expert in urothelial carcinoma, a member of various guidelines panels, and obviously past president of the SUO, a real expert. And why I asked Jeff actually to join us today is there was a recent article in BJU International looking at the comparative effectiveness of neoadjuvant urothelial carcinoma for bladder cancer, as well as for upper urinary tract urothelial carcinoma. And so I wanted to take this opportunity to have Jeff speak a little bit about what this article kind of emphasized and then ask him a few questions. Welcome, Jeff. And thanks again.

Jeffrey Holzbeierlein: Well, thanks, Sam. Thanks for having me on. I really appreciate it and I am excited to join you all today and talk a little bit about this article and perhaps what's behind it and a little bit about the implications moving forward. So I'm going to share my screen here for a second and go ahead and bring up just a couple of slides to sort of review. So as Dr. Chang mentioned, this was an article published in the spring in BJU International, which attempted to examine the comparative effectiveness of neoadjuvant chemotherapy in the bladder and upper tract urinary urothelial carcinoma. The hypothesis and background are that this group of investigators is a multi-center group of investigators from around the world. And the way that we sort of tout this group is that they oftentimes can provide what we would consider real-world experience. So it's from a variety of backgrounds, although many are academics. Different practices are encompassed at these various institutions.

And so again, when we start to report on a variety of different topics, we sort of consider this a little bit more real-world experience. One of the backgrounds is that recently there was a randomized controlled trial, known as the POUT trial, published in The Lancet that demonstrated that adjuvant chemotherapy after nephroureterectomy for locally advanced, and that's either T3 or T4, upper tract urothelial cell carcinoma was associated with improved survival. However, we know that in bladder cancer, neoadjuvant chemotherapy is the standard of care prior to radical cystectomy. And so the question was, does neoadjuvant chemotherapy offer a similar advantage in upper tract urothelial carcinoma similar to bladder cancer?

The endpoints of this trial or this study, which was a retrospective study, was a pathologic complete response as the primary endpoint, and secondary endpoints included pathologic objective response rate, and I'll just sort of reference to that as down-staging, so downstaging to pT0, pTIS through pT1, cancer-specific survival, and overall survival. And what they attempted to do was compare this to similar results in the same cohort of patients as was seen in bladder cancer.

So in summary, in the results, there was no statistically significant improvement in pathologic complete responses in the upper track cohort as compared to the bladder cancer cohort. So, whereas in bladder cancer, neoadjuvant chemotherapy is definitely associated with an improved pathologic complete response rate that was actually not seen in upper tract disease. However, what was statistically improved were pathologic objective response rates, and again, I'll sort of refer to that as downstaging, cancer-specific survival was improved as was overall survival. So similar to bladder cancer, upper tract urothelial carcinoma preceded by neoadjuvant chemotherapy did have improvements in those last three subjects.

Now, upper-track urothelial carcinoma has a multitude of challenges.  And I think everybody is probably familiar with these. First of all, staging is very difficult. So oftentimes, all we really get when we are evaluating a patient with an upper track tumor is really grade. So you are basing many of your decisions, such as neoadjuvant chemotherapy, oftentimes only on grade. Certainly, there may be CT scan findings that may suggest a more advanced pathologic stage, but we are all certainly familiar with CT scan inaccuracies in staging. And so again, this is somewhat of a limitation. Eradication of disease endoscopically is challenging, and this may be one of the reasons why we didn't see as much pathologic down-staging as we might see in bladder cancer. And what I mean specifically by that is that if you are doing a TURBT in bladder cancer, you may resect them to T0 status, whereas that is unlikely in upper tract disease.

In addition, adjuvant local therapies are very challenging. So whereas many patients who may progress in bladder cancer from, say, non-muscle-invasive bladder cancer who had multiple adjuvant local therapies, we really do not usually see these therapies given in upper tract disease. And then we know that genomic analyses that have been done, such as from the TCGA project, suggests that upper tract tumors have more FGFR mutations and cluster more tightly with the luminal infiltrative type rather than the basal type. Again, that's a type that may respond less to neoadjuvant chemotherapy, so again, may explain why we didn't see as many pathologic complete responses. On the flip side, we know that adjuvant chemotherapy, although it has been shown in a randomized controlled trial to be associated with improved survival, that it is not always possible to give it because of decreased renal function. So it is important to understand what neoadjuvant chemotherapy might be able to offer in upper tract disease.

So in conclusion, what I think we can glean from this study is that neoadjuvant platinum-based chemotherapy followed by nephroureterectomy does provide a survival advantage in upper tract urothelial carcinoma similar to bladder cancer. And although we did not see the improved pathologic complete responses, the other endpoints did suggest that neoadjuvant chemotherapy is effective. There is an ongoing randomized controlled trial looking at neoadjuvant chemotherapy prior to radical nephroureterectomy. And so that will hopefully help definitively answer the question, but based on this retrospective study right now, what we would suggest is that neoadjuvant chemotherapy can provide improved outcomes in patients with upper tract urothelial cell carcinoma.

Sam Chang: I really appreciate, Jeff, the effort by this large conglomeration of basically the presenting of, "Okay, here's our data. This is what happens. There's no skin in the game. We just want to see what happens with these individuals." I don't know if you are participating in this neoadjuvant trial, but tell me how the findings of this collaboration have affected kind of what you've decided to do with your upper tract patients. Are you by the book, I'm going to follow level one evidence? Or are you more along the lines of, let me individualize care, and for these individuals, we think neoadjuvant may be better? How do you kind of risk stratify and then determine the next steps in treatment?

Jeffrey Holzbeierlein: Yeah, and I think that's really the question, right, is should we be giving patients neoadjuvant chemotherapy without level one evidence because we do not currently have that, right? So we do have that in bladder cancer, but we do not have it in upper tract urothelial cell carcinoma. We certainly have expected that perhaps the trends are going to be similar to bladder cancer. So where now the trial is showing that adjuvant therapy is better, although you could argue we don't actually have that in bladder cancer, you would expect that maybe neoadjuvant chemotherapy would provide a survival advantage. But I do think that it's, again, important to point out there are very significant differences between urothelial cancer of the upper tract and that of bladder cancer. So there is some, I think, the necessity to actually prove that neoadjuvant chemotherapy is going to be advantageous because if they really cluster, say in a luminal type and they don't really benefit from it, then we certainly do not want to subject people to what is curative, which is going to be nephroureterectomy.

So how do I apply this data? Well, I think this data does suggest again that there is a benefit to giving chemotherapy, particularly locally advanced upper tract disease. So if I see somebody with a high-grade upper tract urothelial carcinoma and I have CT scan findings that make me concerned or even endoscopic findings that make me concerned about probably a locally advanced tumor, then yes, I am going to err on the side of perhaps giving those patients neoadjuvant chemotherapy. Now, conversely, if I see something that's more of a large papillary tumor, doesn't look invasive, in that instance, no, I might not actually give that patient neoadjuvant chemotherapy. I'm going to go ahead and just take them to nephroureterectomy, understanding that there is going to be some overtreatment in that group. They may be high-grade TA or T1 and don't really benefit from chemotherapy. So that's sort of how I'm applying it to my practice these days.

Sam Chang: Yeah. I hate to extrapolate upon extrapolations, but that's very similar to how I think about things, understanding that systemic therapy for non-invasive urothelial, TA, CIS, systemic therapy for those cancers in the bladder unlikely hasn't shown a benefit. So I think similarly for those patients as you say, that appear to be noninvasive, all the caveats that you explained regarding the inability for us to stage actively upper tract disease. But for those that we believe to be non-invasive, the likelihood of systemic therapy being helpful probably is a little bit less, but all conjecture. So along the lines of a more invasive appearing tumor, that's what I tend to do in our practice as well. And that's been our tendency and I take it a step further. Those patients that look, like you, said, locally advanced and/or maybe have nodal disease around the area of dissection or in the upper tract area of distribution, we tend to be more aggressive with neoadjuvant/perhaps therapeutic chemotherapy in that essence, as opposed to moving to nephro-u first, and then following that with adjuvant therapy.

One last question then. How important or what about a patient's renal function? Does that really impact also the decision that you may make if someone is borderline and you really think, "Gosh, if I do remove this renal unit, I really am going to affect the ability to give adjuvant and I'm worried about this? So I'm going to give it upfront." Is that something that you play out in your mind as you contemplate treatment options for these patients?

Jeffrey Holzbeierlein: Yeah, I think absolutely. You're hitting on another critical point and that is that it is possible that we... And I think that's different from bladder cancer, right? You're pointing out the fact that we have that option typically after bladder cancer that we could give adjuvant therapy if we find something we weren't expecting. But that may not always be the case in upper tract disease, because you may end up compromising renal function enough that they are not able to get cisplatin-based chemotherapy. I do think it's important to point out that in the POUT trial, there was still an advantage to giving carboplatin as well.

So again, a little bit of a difference from what we've seen in the bladder cancer world to the upper tract world, which is that carbo does actually seem to offer some benefit, which in the bladder, we would say it typically does not. So yes, though I do think it plays a role. And so if again, I have that patient, I'm thinking possibly they might need chemo, the renal function is maybe a little bit marginal already, I'm probably going to err on the side of giving those patients neoadjuvant chemotherapy, again, hoping that it benefits them because I'm worried I wouldn't be able to give adjuvant.

Sam Chang: Great. Jeff, thank you again for spending some time with us and sharing kind of what the collaborative effort has produced. Tell us, can you give us a kind of a sneak preview or teaser of something that's going to come out next from the group, or is that on a need-to-know basis and we're keeping it hush, hush? Any teasers?

Jeffrey Holzbeierlein: No, I don't know that we have any teasers. I mean, I think we are always looking at a variety of things. And again, I think the whole purpose is sort of providing some, again, what I sort of call real world, but a little bit of context, right, to some of the randomized controlled trials. Sometimes we get those trials and then we have questions either about the design or people don't always feel like they can sort of extrapolate them into practice. And again, the goal of these is to sort of say, "Hey, this is sort of multiple different physicians that are practicing and in a variety of locations that actually have some results that can be supportive of what we've seen in the clinical trials."

Sam Chang: Great. Jeff, thanks again for spending time with us, and I hope to see you in person soon.

Jeffrey Holzbeierlein: Sounds good, Sam. Thank you.