Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. We are quite lucky at this year's AUA 2023 in Chicago to have Dr. Jonathan Coleman. Jonathan is a professor at Memorial Sloan Kettering Cancer Center and an attending surgeon. But for this discussion, most importantly, he was the chair of the AUA guidelines, actually focusing on upper tract urothelial carcinoma, which is actually the first guidelines that have been put out for urothelial carcinoma of the upper tract. So Jonathan, first of all, thank you so much for being here and thank you for chairing such an important initiative. Tell us a little bit about the process of putting together these guidelines.

Jonathan Coleman: Thanks for having me, and thanks for letting me have this opportunity to talk about the new guidelines. The AUA guideline process is very stringent, allowing us to collect a lot of data so that way everything is very strongly evidence-based. I think that's very important. So that way, we're really giving patients the opportunity of being treated with the very best therapies that we have in terms of current informatics. We utilize a group of biostatisticians to scour the data that's published. As look through both retrospective and prospective data to give us the information to build our guidelines off of. So our guideline was really focused on trying to create a standardized process so that all surgeons, all clinicians could handle patients with upper tract disease, which is a very rare cancer and often prone to mismanagement because it's so rare. So that way we could provide a standardized process for evaluating patients in terms of finding their disease, diagnosing, and risk stratifying the types of cancers that they have. That allows us to therefore select the right types of therapies that patients can have as far as whether they need kidney-sparing strategies or whether they need more aggressive strategies in the case of advanced disease.

Sam Chang: So let's focus on, then, some of the nitty-gritty of these guidelines that are being presented this year, actually, at this year's meeting. Let's start off with diagnosis. What are some of the key points regarding diagnostic evaluation of these patients?

Jonathan Coleman: So for any patient who has a suspicion of upper tract urothelial carcinoma, those patients really need the standard, which we all know, which is imaging with axial cross-sectional imaging, and an endoscopic evaluation of the bladder and the upper tract. So we codify that process in terms of which patients really need endoscopic evaluation, and specifically how that endoscopic evaluation should be performed. I think that's a very important key. And that is that for patients who undergo either ureteroscopic evaluation or even percutaneous evaluation, it's a question of collecting the data during that time that allows us to not only document what those patients have, but then be able to also communicate those changes to our other clinicians. So in your note, it should say what type of cancer you saw, where areas of suspicion were seen, whether it's in the ureter, in the upper tract, what the appearance of the tumor looked like, if it's multifocal, and then also radiographic features that you're seeing that helps to add into the model.

Sam Chang: So that helps with the risk stratification. So tell us a little bit about the risk stratification in terms of how that impacts, in terms of future therapies, and choices that are made.

Jonathan Coleman: Based on the standardized approach that we use for endoscopic evaluation of patients [inaudible 00:03:11], we collect data at that time that allows us to then create a risk model in terms of patient's risk for having high grade or advanced cancer. So for patients who have high grade cancer, that defines a high grade or high-risk cohort. For patients with low-risk cancer, that defines a low-risk cohort. But within those two groups, there are substrata that are a little bit more refined in terms of evaluating the patient's risk for having higher stage or more advanced disease.

Sam Chang: So as you consider that... For urologic surgeons, it's been nephroureterectomy, or more recently endoscopic treatment. And now we've got actually topical treatments, those types of things. As you give guidance, we're going to have discussions, and we've had discussions about multidisciplinary care. So where do the medical oncologists come into this?

Jonathan Coleman: Yeah. Good question. The challenges as we went through the guideline is actually we found out that the complexity of managing upper tract cases was a lot more involved than we sort of imagined. From the endoscopic perspective in terms of how cancers are evaluated, treated, and managed. And then also from the medical oncology perspective in terms of how they think about patients.

So in trying to identify those patients who are best suited to therapies like neoadjuvant chemotherapy or adjuvant chemotherapy, multidisciplinary care is necessary to engage the involvement of a medical oncologist. So our risk strata allow us to identify those patients who are at highest risk for having muscle invasive disease at the time of surgery. Those are patients who have multifocal high grade cancers, evidence of invasion based on imaging studies, sessile appearance on endoscopic evaluation, and certainly high grade or high grade pathology either on cytology or on biopsy. In that situation, we know that the risks are much higher, and especially in patients who have underlying CKD or poor kidney function. So in that group of patients, really neoadjuvant strategies should be considered.

Sam Chang: [inaudible 00:05:15].

Jonathan Coleman: And then in the adjuvant setting... Let me just skip to that part for minute.

Sam Chang: Yes.

Jonathan Coleman: So in the adjuvant setting, we have data from the POUT trial. The POUT trial was a large randomized prospective trial looking at the use of adjuvant chemotherapy after surgery for patients specifically with T2 or greater disease. In that trial, it showed very strongly that patients had a benefit in terms of disease-free survival by being treated with adjuvant chemotherapy. Importantly though, that chemotherapy was gemcitabine and cisplatin, whereas gemcitabine and carboplatin was less effective, which is even more rationale for then moving chemotherapy to the neoadjuvant space, especially in patients with underlying CKD.

Sam Chang: Or that underlying type of renal insufficiency that would basically prevent using cisplatin-based therapy. That makes sense. I think importantly with every guideline, we really need to elevate the care for those patients that have high-risk disease, but also for those that have low-risk disease. I think the day of doing a nephroureterectomy for a small, non-invasive, low grade tumor, I think that's obviously overkill. Something that's actually too much. Tell me some of the initiatives to really deescalate the interventions required for low-risk disease.

Jonathan Coleman: There are certainly patients that we overtreat for upper tract disease with nephro-u. Those are patients with low grade cancers, typically those that are unifocal and typically ones that obviously have a papillary appearance, ones that can easily be reached with current technologies like endoscopy. And now importantly, there are new topical therapies that we can provide as well. So there's a lot more in the armamentarium in terms of what we can use to treat those cancers. We've become more skilled as urologists at doing endoscopic procedures, with better digital scopes and so forth. So we do identify that group of patients in the low-risk setting that we call low-risk favorable. That low-risk favorable cohort of patients really should be treated with endoscopic means upfront. If the patient shows signs that the tumor is progressing or is not such a low-risk cancer anymore, in other words it now becomes a multifocal cancer or starts showing up in other parts of the collecting system or has a more sessile appearance, then that grade progression or that risk progression should then be managed with more aggressive options. So-

Sam Chang: Yeah. So-

Jonathan Coleman: ... we have those fail-safes built in.

Sam Chang: So it's important to, I think, then emphasize is this is an iterative process. This is not, "Hey, you're low-risk." You may not necessarily always be low-risk. And so keeping that in mind as you follow these patients. Which then leads to my last question, is surveillance, follow-up. These patients are tricky. I think sometimes we, clinicians, will forget to follow the bladders after an nephroureterectomy. Folks also wonder, what's the best way to follow the upper tract if we do sparing? What are some general guidelines regarding surveillance then in these guidelines?

Jonathan Coleman: So we really had to break that group of patients down into two groups. One is the kidney-sparing group. So in the group of patients where we do endoscopic treatments, the follow-up is going to be slightly different because we have to surveil the upper tract. So that includes endoscopic evaluation that is at a standardized or a routine interval of care after their initial therapy. Then, it gets to a point at some level where you don't need to necessarily endoscope their kidneys if they've been free of disease for a period of time. Then they can move more into imaging follow-up of the upper tract, and then routine follow-up of the bladder.

For patients who've had a nephroureterectomy, really the standardized follow-up is a little bit easier because it's really monitoring the bladder for recurrence in the bladder, which is common. And then also worrying about sites of metastatic disease that may show up. And so there is a process there for both imaging and endoscopic evaluation in those patients. It's broken down based on risk.

In the patients who've undergone nephroureterectomy, our risk strata are even more refined because we have those patients after a nephro-u that are high stage disease versus those that are low stage. So the high stage patients have a little bit more of an intense process in terms of follow-up.

Sam Chang: More frequent.

Jonathan Coleman: Correct.

Sam Chang: Increasing intensity. [inaudible 00:09:14] makes sense. Just like anything in terms of risk-adapting the treatment, you also risk-adapt the follow-up and surveillance. Okay. I told a lie. I said that was my last question. Now this is going to be my last question.

Jonathan Coleman: I've got two points I want to make actually.

Sam Chang: [inaudible 00:09:27] okay.

Jonathan Coleman: But yeah, [inaudible 00:09:27].

Sam Chang: So start off with your two points. That'll be important.

Jonathan Coleman: So two points I wanted to really make. One is that a big part of the guidelines that we bring into play is something that's brand new, and that is screening for patients for Lynch syndrome. So that's a very important aspect and probably one of the main things that the guidelines bring right to the forefront. That is that lynch syndrome is extremely common in patients with upper tract disease. So Lynch syndrome is a multi-organ inherited disease syndrome that's also called hereditary nonpolyposis colon cancer. But it's patients with colon cancer that runs in their families, but also patients are at risk for endometrial cancers, ovarian cancers in women, pancreatic cancers, biliary cancers, and stomach cancers, and gastric cancer. But it's interesting because all the other societies that are out there have already mandated or required universal testing for those cancers. So gastric cancers, endometrial cancers are supposed to get universally tested for MMR genes on immunohistochemistry to look for Lynch. Yet, the prevalence of Lynch in those patients, in patients with gastric cancer-

Sam Chang: Is much lower than...

Jonathan Coleman: .... less than 3%.

Sam Chang: Yeah.

Jonathan Coleman: The patients who have upper tract disease, in terms of their risk of having Lynch, is around 9 to 12%. So three to four times higher than what you would see in gastric cancer. And yet we don't routinely screen those patients. So we're now mandating universal screening, universal testing through whatever means you want. We didn't sort of land on any particular one. MMR testing is sort of standard. MSI testing can also be done standardized. They're not genetic tests, but they are at least screening tests that help you to identify those patients. That's very important.

Sam Chang: Yeah. So that's your first important point. Your second point that you wanted [inaudible 00:11:06].

Jonathan Coleman: Second point was the use of adjuvant therapy in the bladder after a nephro-u. So this is something that's not always common, but there is data from not only AUGMENT trial, but several other trials that show that giving mitomycin in the bladder after a nephroureterectomy can decrease the rate of bladder recurrences. That can be clinically important for patients. Meaning that they have less impactive therapies afterwards at the time of [inaudible 00:11:28] endoscopy. And so we mandated that that also should be routinely performed for patients.

Sam Chang: Yeah. Two important points, for sure. As you complete the guidelines... And this gets to my last question, which I said I didn't have. But as you complete guidelines and you've been involved in other guidelines, it always begs more questions, kind of future areas of research, future areas of promise, future areas of concern. Highlight some of those that you think are important to actually raise.

Jonathan Coleman: Yeah. I think one of the biggest challenges we have in upper tract disease is our ability to accurately grade cancers and accurately stage those cancers upfront. So there's a lot of work being done right now looking at, say, urinary markers that may be used for identifying high grade or high stage disease. Also looking at certain signatures in those cancers that may be targetable in terms of pathways. And now because Lynch is an issue in upper tract disease, we know that certain strategies in terms of immunotherapies may be appropriate in those patients. So I think finding those patients, especially with non-invasive techniques, such as urine-based markers is going to be important. And there are a lot of labs that are now working on that.

Sam Chang: Well, Jonathan, thank you so much for spending some time with us. I know as a new guideline, as a new oncology guideline, this is going to gather and has gathered much attention, and deservedly so. And your leadership on the guidelines' panel truly came through in terms of the changes that have been made and significant contributions. So thanks from all of us. And thank you for spending some time with us.

Jonathan Coleman: Well, thanks, Sam. It was a pleasure talking to you. And thanks so much for the opportunity.