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Sam Chang: Hello everyone, this is Sam Chang. I'm one of the urologists in Nashville, Tennessee. And today we have a real opportunity here to go over case scenarios with Dr. Surena Matin. Surena is the Monteleone Foundation Professor involving different types of research, but a named Professor at MD Anderson Cancer Center. He really doesn't need an introduction. Everyone knows his contributions to this field. And so Surena, I think you've got a PowerPoint that you were going to discuss because we are actually going to go over a scenario here. And I think it's very real world, you were kind enough to share with us to basically give an idea of how you initially diagnose, manage, and then survey those patients. So why don't we go ahead and start with your talk?

Surena Matin: Absolutely. Sam, Hey, listen, thanks so much for this invitation. 

Sam Chang: It looks great.

Surena Matin: Great. So, Sam, I don't want you to walk away because I'm going to have a couple of questions for you along the way. All right.

Sam Chang: I'm not falling asleep. I'm here.

Surena Matin: I'm also very curious to also see what your thoughts are.

So I'm going to present a case on low grade, upper tract, urothelial cancer, and this is not an overt success story and it's on purpose because I think it highlights the challenges that we face dealing with this disease. And I will be discussing, off-label use of some agents here at some point, possibly.

So this is a 71-year-old patient who presented with microhematuria and this was investigated by another doctor and he was found to have a 7 mm lesion in the distal, right ureter. You can see it on the CT scan.

Now it's interesting, he had a history of a right hemicolectomy for a lymph node, metastatic colon cancer. And they did immunohistochemistry on these, which is considered to be the standard of care for mismatch repair proteins. And, he was found to have an absent expression of PMS2 and MLH1 proteins. And this was an MSI-high tumor. He does have some comorbidities, but he's overall well-compensated, has a good performance status, some tobacco history, but not an active smoker, kidney function is quite good. And so a couple of questions for you all to think about, but there is a reason why I presented that story under immunohistochemistry for colon cancer. And Sam can I pimp you here for a second?

Sam Chang: Sure.

Surena Matin: What are your thoughts about that?

Sam Chang: Well, honestly, five or 10 years ago, we wouldn't have really thought about this patient. It's actually a lot of work that you have helped lead in terms of evaluation and giving to practicing urologists in terms of keeping in mind, Lynch-related tumors, malignancies, age group, all those things coming into my mind. So you have to consider that this patient, with these changes, with those mutations that you outlined, you have to wonder if this patient someone with Lynch syndrome, and in all honesty, these are patients that we would refer to our hereditary, actually cancer clinic.

Surena Matin: Exactly. [crosstalk 00:03:27]

Sam Chang: That's what we would do.

Surena Matin: That was the second question. So that's exactly right. And it's relevant for upper tract because we think, about 5% of our upper tract patients have undiagnosed Lynch syndrome. That is not yet validated, but that's based on some retrospective work that we've done, but we do certainly... the upper tract cancer is the third, most common cancer in this particular population. So absolutely we are worried about the possibility of Lynch syndrome. As it turns out, this patient was referred for genetic counseling. Again, in the colorectal world, this is considered to be the standard of care. They did do genetic counseling and ruled out Lynch syndrome. And what this means is that this was a somatic mutation, it is not an inheritable mutation that the patient had.

And so this is going back now to November 2018. I performed cystoscopy, ureteroscopy, retrograde pyelograms.

This picture is a little fuzzy and I apologize, but it's about a one and a half centimeter papillary tumor, clearly on a stalk. It was unifocal. I looked throughout the entire collecting system. He did have a tight urethral orifice that I had to dilate. The tumor was able to be removed completely with a basket and then I laser ablated the entire base. As a routine, I always give these patients intravesicular chemotherapy afterward, the same standard as we would for a bladder cancer. And these are just some of the images from the retrograde pyelogram at the time.

And to just talk about my approach to this, for a first-time patient, I do a more formal evaluation with a good retrograde like this. In this case, I'm using..., you can see an acorn tip catheter because I knew it was a very distal lesion, and I just didn't want to manipulate anything until I looked at it and had a good roadmap.

Now you notice that the ureter right above the tumor is really skinny there, and that's going to end up becoming relevant down the line. Now, the other thing that I do, and this is something that I developed based on the clinical trial we did with Mitogel, now called Jelmyto. For that, we have to do a very formal washing before retrogrades and then do retrogrades. So I've just sort of developed that habit as a result. And so if I don't know what kind of tumor I'm dealing with, I always get washings first. I may not necessarily send it, but I do find that sometimes it's a nice adjuvant, sort of additional piece of information, especially if you get a scan to biopsy or it's a nondiagnostic biopsy or biopsies is low grade, but the cytology comes back high grade, then it can help add to our limited sampling.

Sam Chang: So, two excellent points there Surena, that I always learned from these, is one, the use routinely of any upper tract treatment biopsy, that type of thing that you use [each therapy 00:06:22] chemotherapy. The second is this Royal flush, ureteral catheter, which I'm not familiar with, was that made by a certain company? Or is this something that you guys came up with? Give me two seconds on that here.

Surena Matin: Yeah. It's commercially available. I think Cook Urologic makes it. And I have no business agreements with them. [crosstalk 00:06:49]. What I really like about it is it's got multiple side holes at the tip. And so, with an open-ended when you put it up there and you're trying to get washings, then the mucosa just always stops it up. With this, it's a total breeze. You could even do washings in the ureter, of course, the return isn't quite as good. So that's my workhorse, ureteral catheter for any kind of installation or washing that I want to do.

Sam Chang: Let me with that in mind... I oftentimes struggle with this is, I'm worried about the contrast that I inject prior to a washing, is that going to affect my washing? And so basically if they've had a previous stent that makes things easier in terms of here's my guesstimate of where my renal pelvis is, but, to be honest, what I do because I really want to be... I use very dilute contrast, just to give me a little bit of an idea that I'm in the renal pelvis or proximal ureter. And then just as you say, I end up sliding that ureteral catheter up and down because it is hard to collect the urine back after five, seven CC's of normal saline. Tell me kind of the nuances regarding how you do this for the first time, not sure what is going, on type of patient.

Surena Matin: No, I think the way you do it is fine because so again, with mine, it's been developed based on this very rigorous clinical trial that we were involved with. And so what I'll do is pass a wire up and then pass up the Royal Flush Catheter. And just looking at the angulation of it, because then you can kind of tell when it's in the renal pelvis, now you may not always be perfect, but I'm usually pretty close. I inject five CCs at a time, and I alternate in terms of allowing passive drip and then actively aspirating because I'm also impatient and I don't want to sit there all day.

But I try to collect like 30, 40 CC's of a wash. [crosstalk 00:08:59] With this Royal Flush, it is not that difficult to do. And what I do is, if I think for example, I'm in the upper infundibulum, I'll pull it down like an inch and do some more washings and I'll even go to the proximal ureter. I don't go any lower than that. I mean, you could, but the way I do it, I have no question that there is no contamination from the bladder. I have no doubt so that when I get a result, I know with certainty it's from the upper tract.

Sam Chang: Yeah. Hugely important. Good point. Go ahead. Thanks.

Surena Matin: But I think the way you're doing it, is fine too. As long as you feel like your cytology results are reliable, that's what counts. And the way I was doing it before was a combination of post undiluted contrast and sometimes doing it through the ureteroscope. And then what happens with the ureteroscope is, the working channel is so skinny, it's 3 french, and I think we are getting so much turbulence along that length, you're just lysing the cells and all you are getting is stripped nuclei. So it's convenient, but it's not a good diagnostic.

Sam Chang:  Good points.

Surena Matin: So yeah after I do the washing, I do retrogrades and then again, if it's a first-timer, I'll do a semi-rigid to clear as much of the ureter as I can. And then I'll put up a flexible and... if I'm doing biopsies, I'll put up an access sheath. I think it's a critical aspect of being able to get adequate samples and then, usually leave a stent.  And I was giving patients the option of self-removal versus coming back for a cysto, I don't really give them the option anymore. I just tell them they are going to take it out, but I have long instructions for them.

Sam Chang: Good points.

Surena Matin:
And I do this a lot, I have a wonderful department, so I pretty much see 80%, 90% of the upper tract cases. We have another faculty here, [Marotta DB 00:11:01], who has been awesome and has been able to offload a lot of them and is getting a lot of experience with the two, but, I'll do three to five or six upper tract endoscopies in a week, depending on the week. As you know, they are time consuming, right?

Sam Chang: Yes.

Surena Matin: So going back to [that patient 00:11:21]...

Sam Chang: Yeah, go ahead.

Surena Matin: Can I go back?

Sam Chang: Yeah.

Surena Matin: Three months later, he comes back and he's got a bladder neck tumor that we do a TURBT on. And he's got this tiny tumor in this lower calyx. You can kind of see this fuzzy part of it here. And I think there is some villi stuff on the calyx, you can see here, we've lasered it. And so I gave him some more intravesical gemcitabine, but now he's got both recurrent, upper tract cancer, of course it's low grade. And the bladder has tumors now also. And Sam, what would you do in this case?

Sam Chang: Oh, I probably would just re-scope in a few months.

Surena Matin: Yeah. So as for his first surveillance of scope, he had bladder cancer and upper tract cancer. We discussed surveillance. I talked about treating the bladder only, and then also possibly giving him upper tract installations. At that time, the clinical trial with Jelmyto was over, so it was not commercially available. So that was not an option. Now, he didn't want to do upper track treatments and we just elected to give intravesical gemcitabine, but he wanted to leave the stent in place. And that wasn't necessarily my decision. And he tolerated this while we removed the stent. But I put that question down there in terms of treating the upper tract with intravesicular therapy. And I know a lot of people still do this or think about it. I honestly don't think it works.

Sam Chang: I agree with you. Glad you said that. Because I was going to say, I don't think it works. I honestly think that it treats the physician more than the patient.

Surena Matin: Yeah. And as we will see, it certainly did that in this case as well. And so I certainly... It's not a reliable way of delivering chemotherapy to the site. So, we don't really... This is the one time I did it. And again, I was talked into by the patient.

Sam Chang: Yeah. I mean, to tell you the truth Surena, I do it. I don't really think it works because I've been stuck in the past, with not a lot of options. So gosh, the way I phrased it to patients is it's... and I've just had a patient with horseshoe kidney, actually with disease, both sides in the bladder. And I said, "it's not going to hurt, but I don't think it's going to help." And so that is exactly where I am, about to re-scope, and he's gotten gemcitabine as well. So we'll see. So what happened with this?

Surena Matin: So, three months later, and this is a second surveillance ureteroscopy, now he's got greater than eight upper tract tumors all throughout the collecting system. And so again, I did total laser ablation of all the visible tumors. Now he's developing a urethral stricture, right where we saw that narrowing. And I had to dilate it, place the stent, kidney function is still good. And so now it's becoming...

Basically, we started off with this one little tumor and it's like watching evolution in play here, where it's just basically cloned itself throughout the right upper tract. And so I offered him a nephroureterectomy when it recurred. Of course, at this point, there was no disease. I didn't think, so I wasn't going to do it then. We, again talked about adjuvant chemotherapy, delivering it directly either by nephrostomy tube or doing a weekly office cystoscopy and placing the ureteral catheter or that Royal flush catheter. And then he initially wanted a nephroureterectomy but then he decided against it and we decided to do a confirmatory ureteroscopy because he had so many tumors, similar to the bladder, where you think you got it all, but there was so many, it's possible, you missed a few, right. So...

Sam Chang: Really honest and very appreciate that Surena because we miss them all the time in the bladder, despite all the things that we are trying to do with narrowband imaging or with blue light, you still miss tumors when there is high volume, you just can't avoid that. And even more difficult as you evaluate the upper tract, your visualization is for sure more difficult to see everything. So I think very honestly, it really makes sense. So when you went back and it showed small tumors throughout?

Surena Matin: Yeah. A bunch of tiny, sort of early ones. Exactly, and so this is the biology of these, I'm not sure we can fully explain yet. I guess we're starting to understand a little bit, but these are low grade, but what is it about them that makes them so darn sticky and so likely to seed themselves and form?. Whereas there are others, that same thing you do to one centimeter ureteral cancer and they never recur.

Sam Chang: They don't come back. Yeah, no, it's really a good point. As you go to your next slide here, sorry, now I'm going to ask you a question here. So what do you, at this point as you're going through this, how do you and how often do you evaluate the contralateral side?

Surena Matin: Great question. In the past, I used to get talked into doing it and I would say more than 50% of the time I ended up regretting it because it invariably was Murphy's Law, where it was the good side, where the first domino fell with something, it was a tight orifice, the patient drove 12 hours from somewhere and their family had to take off work and they wanted me to do it all at once. So then next thing you know, they got a stricture on the good side. So I've developed antibodies to doing ureteral. So I only do a scope on indication. There has got to be a cause. [crosstalk].

Sam Chang: That's so good to hear.  It's like everything, you always agree with those that agree with you. So that has been a practice that I developed. I used to honestly [wrote 00:17:29], go and do a retrograde or do a ureteroscopy to evaluate the contralateral side because I was so worried about the contralateral side. I evolve that totally 180 degrees and you have got to make me something, blood come from that orifice, a finding on CTU, something. And I'm a big believer that CTU in those patients that have good enough renal function or MRU for those that don't, is honestly much better than a retrograde in my opinion, and much better than, than sort of mucking up something that is okay. Just like you said. So I appreciate that. So I think that's an important point here.

You started now with this patient, with then the antegrade treatment through a nephroscopy tube, it looks like?

Surena Matin: Yeah, that's correct. Then I ask the radiology team to put that into that upper pole calyx so that we could try to get coverage throughout the whole system. We have a great nursing team, they've had a lot of experience with these. And so they drip it in very slowly over an hour, usually an hour and a half. That's how we do it to try to make up for the lack of contact time, it's not in a reservoir. Right? So, and you can use the higher volume of gemcitabine as well. I don't think there is anything wrong with it. In fact, I've been thinking maybe I should have been doing that from the beginning, just because you're just getting more chemo contact basically. And I do have patients change their position about every 15 minutes, who knows if it's voodoo or what, but I just feel like I'm doing all I can to get maximum contact there.

Sam Chang: Makes sense.

Surena Matin: So we think it was successful. I mean, three months later, their ureteroscopy is negative. So I recommended monthly maintenance. I said, let's at least do three monthly maintenance just to kind of lock in the results. And at this point, we removed the nephrostomy tube, and so I did that in the office. We're lucky that we have fluoroscopy in the office, so I could do it with them awake. I put up this beacon tip, you can see it here, and I do a light retrograde, so I can make sure that it goes into that upper pole calyx.

Sam Chang: Same concept that dripping down. Okay.

Surena Matin:  Exactly.  We put a Foley in and tied the two together so that we make sure it doesn't get dislodged. And then he goes over across the hallway to where the treatment room is and the nurses start dripping it in. And he has developed this stricture now in his distal ureter, as you can see, but he's tolerating this, the procedure is okay, despite that. So keeping his kidney function.

So anyway, to summarize what happens over the next eight months, we do next after the three maintenance courses, we do another surveillance, he's got a tiny tumor on his trigone, otherwise, it looks good. We're pretty happy. But then three months later, it comes back and he's got multiple tumors, his prostatic urethra is now seeded as well. And we see multiple defects in his CT urogram.

So TURBT confirms these multiple TA low-grade tumors, including bladder neck, prostatic urethra, and then again, multiple tumors throughout the upper tract. And so at this point, Jelmyto had just become available a month earlier. I also was considering just switching drug regimens because, and I'll maybe talk about that in a minute, but then also the option of nephroureterectomy. The only other thing is though, by this point, he had so many manipulations and plus with the resection of the prostate and bladder neck, that he's just getting worse LUTS and the irritative symptoms are really problematic. It's resistant to ditropan and levsin, and his quality of life clearly is declining. And so with that, the pandemic was going on at this time as well. So it just made sense to de-escalate. I mean, we're dealing with low-grade disease and of course, everybody was deescalating big time during this time.

Sam Chang:  Yes.

Surena Matin:  And so in this case, I didn't think there was a detriment. In fact, cancer-wise, I thought it was going to be okay. And if anything, he needed a break from us poking him. And so over the next couple of months, we just had discussions about what to do. And my thought was, I can't really do anything to the upper tract until I control the bladder. I'm not about to go do a nephro and do a bladder cuff in a bladder with active disease. So my thought was to give him BCG, keeping in mind his symptoms potentially were going to get worse, but we were able to get myrbetriq on board with him.

But the rationale for this is, the data that's coming to light here with the upper tract is that most of them are luminal and they appear to be immunologically cold. And so that possibly, maybe, explains why topical chemotherapy seems to work as an adjuvant and traditionally BCG hasn't. However, you do get some of these, maybe it's roughly 20% or 30%, we think based on the data that we have, that is just coming out now that are basal. And so maybe more immunologically responsive. So my thought was, well, maybe this is kind of chemoresistant, but maybe it will respond to BCG. And so that was my thought for switching that up, but also what other options do I have?

Sam Chang: Exactly. No, exactly.

Surena Matin: So we give him BCG. He actually tolerated it well. A follow-up cysto showed two tiny bladder tumors. I didn't consider that a failure necessarily. Again, they were low grade. I think we just fulgurated them in the office basically. And then we decided to give the first maintenance and then reassess in three months. We had a delay by a couple of months because of the pandemic. And then basically what we see is some recurrent bladder tumor, not terrible, but some, but you can see the upper tract here on this retrograde is just full of tumor. There are tumors everywhere. The biggest problem was though I can't even pass the scope up anymore. I tried dilating it. I didn't want to get the balloon in the presence of a tumor there and splitting the ureter. And so we tried some general dilation techniques, but I just could not... actually I could get the scope up, but the problem with that situation is number one, I can't really do biopsies well in that setting without an access sheath.

Secondly, and I had this as a major complication with one frail patient in the past, where it persisted. The problem is you have a tight ureter against the scope. And meanwhile, you've got irrigation going in under pressure. That irrigant has nowhere to go than to go through the [pile of venus 00:24:22] and [pile of 00:24:22] lymphatic system. And so many years ago, again, it was one of these patients who traveled a long way and he couldn't tolerate too many anesthesia things. So we were trying to do everything at once and you know, that patient literally developed ascites from what we did. And, so, which was just horrible. And so that's the pitfall of persisting in a case like this. So I knew it was time to get out of dodge.  There was one tumor that I was able to biopsy just to confirm that there wasn't, high grade, and of course, we did washings.

But basically at this point, just to cut to the chase, the patient ultimately agreed to a nephroureterectomy.  I did a cystoscopy just before the nephroureterectomy just to make sure the bladder was clear. And then we did a robotic nephroureterectomy with a bladder cuff, gave him intravesicular gemcitabine, just because that's what we give everybody, but who knows how...

Sam Chang:  Right, agreed.

Suren Matin: And of course, the pathology, thankfully it did not progress or grade progress, but there was high volume disease there, multifocal TA, there was some higher lymph nodes that we just removed incidentally. I didn't go out of my way to remove them. The margins were all negative, so I should be seeing the patient back for a follow-up soon. But what I really wanted to highlight here was the various challenges of managing someone with low-grade disease that we don't really... you know, we kind of skim over these guidelines and in papers, which in biology like this, that can be this fulminant recurrent disease that we... chemo doesn't seem to touch very well. Maybe it will change with Jelmyto, we don't know. For patients with high volume disease, it's still a problem. Yes, it's easier to go around saying we shouldn't take out kidneys for low grade, but if you're dealing with like a four or five-centimeter tumor, even if you're going to do percutaneous resection, it's going to be a challenge there.

So, and then there are the consequences of what we do. Stricture is well-recognized and still an issue even with Jelmyto, seeding the bladder. The ureteroscopic intensity that is recommended by expert opinion, quite honestly, I think it's too much. I do not do it that frequently. In this case, we had to, just because of the nature of the disease, but I just think it's too much for these... especially they are older and frail patients. There is a lot of data that each anesthesia you do affects their cognitive ability, which is a big problem in that age group. And then, they are tortured by bladder symptoms, and then so is the urology clinic team that has to handle all the phone calls of course, but it really, it's an impact on their quality of life. So there is no question that nephroureterectomy is likely over-utilized for many of these low-grade cases, but it's still a better option, sometimes compared to all these other factors that come into play when we elect to do an endoscopy.

Sam Chang: Well, Surena, that was fantastic. I think there are some key points that you have emphasized that really make the most sense there. And I think it's at least the question of; you don't know what you don't know and, and you know what you know, and in low-grade disease, a lot of times you don't know what you don't know. And what I mean by that is, just as you said, there are some low grade tumors that you ablate, that you laser that follow the guidelines. Oh, you do well and you follow up and they are, they're okay. And they're okay for a while. I love your point regarding perhaps the over the instrumentation of these patients. Sure, early on, maybe evaluated three months. But then after that, the most often I will go would be six months in these patients.

I think CTU, MRU, I think is really effective, but gosh, for these people that keep either having carpeting or have recurrent bulky tumors that you still think are low grade, but you probably haven't sampled them totally. Just to say, I'm worried and I think you're exactly right. That nephroureterectomy is the best option for them. The tricky patients are those patients with the renal insufficiency that in all honesty, if they are doing okay, symptomatically, I let them have tumors that slowly keep growing and hopefully it is slow. And, we have to be almost forced into doing a nephroureterectomy once they start having symptoms or that type of thing. But it's the individualized care that you mentioned I think is really important. And I really want to thank you for the highlights that you made of... In all honesty, we see just as many, if not more of these low grade tumors.

And you're absolutely right. I think with laparoscopy and with a robot, a lot more nephroureterectomies are being done. It's easier technically, but is it the right thing? I think if anything, we need to really individualize that care.

Surena Matin:  Absolutely.

Sam Chang:  So again, thank you so much for your time and for your insights and for your honesty. I mean, if anything, I think this highlights... This is one of the leading surgeons in the world at one of the leading cancer Institutes that basically maps out some of the struggles that I think many of us have had, and it highlights the importance of careful treatment and individualized care. So thanks again Surena. Very much appreciated.

Surena Matin: Thanks so much, Sam.

Sam Chang: All right. Thank you.