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Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Peter Black, a Professor in the Department of Urologic Sciences at the University of British Columbia in Vancouver. Thank you so much for joining me today.

Peter Black: It's a real pleasure to be here. Thank you.

Alicia Morgans: Well, thank you. I wanted to speak with you about upper tract disease because this, I think, in all that we do for urothelial cancer can be one of the more challenging, at least in terms of diagnostics, and also in other ways. But to focus on the challenges in diagnosis, specifically, what are some of the challenges that you think about as you're facing patients with upper tract disease?

Peter Black: I think the big issue with upper tract disease is getting tissue, tissue to confirm the diagnosis, that it is actually urothelial carcinoma, but also tissue to risk stratify, especially to get the grade, establish the stage, and then decide on best treatment.

So I think traditionally, we've often just made a diagnosis based on imaging, usually a CT scan. And then the urologist would proceed to do a nephroureterectomy and just remove the kidney and the entire urothelium on that side, which is over-treatment for a lot of patients. It wastes potentially a healthy kidney. There's always a risk, of course, that the patient actually doesn't have urothelial carcinoma, that it was something else, that filling defect on the CT was something else. And I think we also recognize that patients with more advanced disease have very poor outcomes with just nephroureterectomy. Removing the kidney may even remove the opportunity to give chemotherapy, cisplatin-based chemotherapy, so there's been a push over the last several years to give more neoadjuvant chemotherapy and to do that, of course, you need accurate diagnosis and risk stratification. 

Alicia Morgans: Absolutely. What are ways that you think about trying to do this? Are there technical advances that have been made or techniques that you use to try to get that tissue diagnosis without just removing the entire kidney? 

Peter Black: Yeah, well, the big issue is ureteroscopy. That's how we do it. We go in with the scopes from below, retrograde, and certainly, the technologies of ureteroscopy have improved. Digital ureteroscopy, for example, gives you much better picture. We still have big issues with the size of the instruments, and that's ultimately the limitation. 

The working channels on the ureteroscopes are small, so the biopsy forceps are small. You get tiny pieces of tissue if anything at all, and we ask a lot of our pathologists with those pieces of tissues. But there have been some improvements, so we will often, for example, we'll use a ureteral access sheath so that you can go up and down repeatedly with the scope, so you can get ... multiple small pieces perhaps will help you to make a better diagnosis and staging and grading. 

People are also, for example, using baskets. Baskets that we'd usually use for stones you can pull off a piece of tumor and get a better tissue diagnosis. And then there are new forceps. For example, there's one called BIGopsy that you have to backload into the scope, so it doesn't go through the working channel. It's too big to go through the working channel, but you can backload in, and then you can go up the access sheath without hurting anything and you can get a nice robust piece of tissue for biopsy. 

Alicia Morgans: Absolutely. When you think about that, now you're a urologist, so you wouldn't necessarily be doing chemotherapy, though sometimes I know things are different in different places, but if you had this diagnosis from your different biopsy techniques and if you had some upper tract lesion, what are your thoughts ... if you can leave that kidney in place, is your group typically giving you adjuvant chemotherapy now for these upper tract lesions? 

Peter Black: Yeah, I think anything that looks a little bit higher risk, I think we really should be giving more neoadjuvant chemotherapy. The problem is there's not a lot of study evidence to back that. The purists would say without good evidence, we shouldn't be doing it. We borrow from bladder cancer. We know that neoadjuvant cisplatin-based chemo is effective in bladder cancer, and therefore think it should be effective here. And it's even more important here because the outcomes are poor, but also because patients lose renal function, and so a portion will become ineligible for cisplatin-based chemo after surgery. 

The problem is actually defining which patients should get it. We know if we do a biopsy and it's high-grade tumor, that about two-thirds of those patients will have at least muscle-invasive disease. But the other third, if you base it on grade alone, the other third are potentially over-treated. So we look at additional things, presence of hydronephrosis, for example. Location can make a difference. Different risk factors and there are a couple of models employing different risk factors to decide whether a patient should get neoadjuvant chemo or not. 

I don't think the word has really spread amongst urologists that they should be thinking of this, so I think we do have to do a better job getting that message out.

Alicia Morgans: Absolutely. I think we in medical oncology, at least since one of our cooperative group trials, are trying to do this more pre-op neoadjuvant type of an approach. We do focus on the high-grade lesions, but like you said, a majority are going to be muscle-invasive, but it can be hard to ... you can't define that before an operative procedure really, even with some of your fancy biopsy techniques. 

Peter Black: Yeah, and imaging, of course, also has it's ... that's ultimately ... the first problem is that imaging has limitations. So you can't really tell based on imaging. And then you have the problem of small instruments and getting tissue. It's funny, in bladder cancer we say we should be doing neoadjuvant chemo because that's where the data is, and adjuvant, we don't really have the data. In upper tract, we actually have good data for adjuvant, now with the POUT trial, but we still think that it probably would be better to do neoadjuvant because of the issue of losing renal function. 

Alicia Morgans: Absolutely, and in POUT, we saw that really the benefit seemed to be with cisplatin, and so we do need to have a person who can tolerate cisplatin in order to get cisplatin to give us any benefit for that patient. 

What else should we know about the diagnosis of upper tract disease? What else is really critically important that seems to be lost right now out there, in terms of what we know and understand? 

Peter Black: There are different things. One thing that's coming to light more and more recently is that when we do ureteroscopy for a diagnosis, for biopsy, that the subsequent rate of bladder recurrence is increased. So it makes sense, again in absence of clinical trial data, to actually give a single dose of chemotherapy at the time of the ureteroscopic biopsy. That's something that people are starting to do, again with the caveat that we don't have trial evidence. 

There are things like that. There are new imaging techniques coming along, so we use fluorescent cystoscopy in the bladder a lot, and there's narrow-band imaging and fluorescent cytoscopy is not yet available for the upper tract, but narrow-band imaging adds an element. There are also new technologies coming along like endoluminal ultrasound, which the group at MD Anderson has tested, and there's certainly a need for refinement of the tools before we can actually use it widely. But I think technology will certainly help us moving forward. 

Alicia Morgans: Absolutely. If you had to have one take-home message for all of this, what would it be when we're thinking about diagnosis and the dilemmas that exist in upper tract urothelial cancer? 

Peter Black: Yeah, I think the big message would be it's not one size fits all. We should not just take out every kidney that has a filling defect. We need to risk stratify and treat accordingly, whether it's endoscopic management in lower risk or chemo before surgery in higher risk. There will certainly be a large proportion in the middle where we do want to do a nephroureterectomy, and maybe not every patient requires a biopsy if it's obvious and they're not chemo-eligible, and they're not going to have endoscopic management. There may be some patients who don't need it, but we need to develop more accurate algorithms to run through that. 

Alicia Morgans: Absolutely. And just to sort of piggyback on that, systematizing or making algorithms to do things the way that we believe they should be done in the proper way, I think, is really going to be critical. So I appreciate so much that you took the time to think that through with us as we make sure that this kind of more standardized approach gets its way out into the community and is something that patients see on a day-to-day basis, because it can be hard, if you don't know how to proceed, it can be hard if you don't have some guidance. So thank you so much for providing yours. 

Peter Black: My pleasure.