Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt University. I have the great honor and privilege actually to introduce one of the leaders in European urology and actually one of the international leaders when talking about urothelial carcinoma, and that is Professor Paolo Gontero. Professor Gontero is the Chair of the Department of Urology at Molinette Hospital in Torino, Italy, and is a professor at the University of Torino. So we've asked Professor Gontero to actually enlighten us on the new EAU guidelines to upper tract urothelial carcinoma. It's been recently updated, and he's been kind enough to share some slides as he is one of the lead authors. So dear Paolo, welcome, and thank you for spending some time with us and we look forward to your presentation.

Paolo Gontero: Thank you very much, Sam, Professor Chang, and thank you very much for... it's a great honor for me to be invited, and we should thank also UroToday for this kind invitation. It's a great honor for me. I think I will try to go through here with my conflicts. I will try to go through three main topics that have been subject to some little revision, I would say, because, as we all know, UTUC is a field where evidence, strong evidence is still lacking. And so I'd like to address a little bit about the relationship between UTUC and genetics, because we know that UTUC, while being rare in itself with two cases out of 100,000, and this is at least in Europe, actually is the third most common cancer of the so-called Lynch syndrome. And this is after colorectal and endometrial cancer.

We all know that Lynch syndrome is basically caused by germline mutation in one of the four so-called mismatch repair genes. We can actually suspect quite easily this mutation has a loss of expression of the genes by doing immunohistochemistry. But if we do immunohistochemistry in all sporadic UTUC, we will come across up to 9% of cases that have some alteration UTUCs, and this beings a strong genetic component, I think. And if we do, we check for DNA sequencing of the germline mutation of the mismatch repair gene, we will find around 4 to 5% of UTUC that have actually strong link with Lynch syndrome.

So, under this premises, the guidelines panel last year has just a little bit refined what should be the workflow for patients that present with UTUC. And the recommendation, which is actually a weaker recommendation, because actually, the evidence is not so strong, is that patients presented with UTUC should receive a medical history that is focused to rule out Lynch syndrome, and young age, personal history of Lynch-related cancers or first-degree relatives with a history of Lynch-related cancer, particularly when they're young, actually should prompt germline DNA sequencing mutation search.

But the question is still open on what should we do when in cases of a sporadic UTUC where we do not have a strong history of Lynch syndrome? Should we do immunohistochemistry in all cases and look for this 9% chance of potential Lynch syndrome? I think the question is still open, and probably we need really more evidence, but I think that this is really something that should not be overlooked, particularly really strong implications set in our daily clinical practice.

Concerning the stratification of UTUC, you know that in 2017 that the EAU panel proposed that this categorization in low and high risk, and this was actually designed in order to select those patients who would be good candidates for conservative treatment. But there is a problem because while these individual variables have been individually validated, all set of these variables that account for low or high risk has not undergone really a validation. Recently, there had been a study that has actually tried, attempt to validate this categorization, and this study, again, is based on a retrospective series of 1000 to 100 UTUC patients that received nephroureterectomy. And what they found is actually that the EAU categorization has a 70% accuracy to predict patients who have an organ-confined, noninvasive UTUC, which are the patients that more likely could receive conservative treatment.

But what they found also of interest in this study, and this has just been published this year, is that they actually proposed a three-tier categorization of UTUC, low, intermediate, and high risk. They added the intermediate risk, just mimicking the non-invasive cancer categorization. And this category accounts also for multifocal disease in patients who had a previous cystectomy. This kind of category has a higher risk than the low-risk patients, but could be potentially amenable for conservative treatment.

What about neoadjuvant and adjuvant treatment after nephroureterectomy? Well, if we look to the outcome of UTUC in the last 20 years, there has been little improvement in the prognosis, and perioperative treatment as being not very common. This is due to a number of factors, that the patients that receive radical nephroureterectomy, many of these patients are actually unfit for adjuvant treatment.

Now, the question is, what about giving neoadjuvant chemotherapy? This is working very well in muscle-invasive bladder cancer. I'm talking about obviously locally advanced upper tract urothelial cancer. Well, by doing so, by giving a cisplatin-based neoadjuvant chemotherapy, there is a partial response rate of 11%, which is clearly lower than that reportedly for muscle-invasive bladder cancer. There is a downstaging of 33%, and there is an improvement in cancer-specific survival, but you have to realize that this is based on mainly retrospective studies, or at best, phase two studies. And there is some dark side of doing neoadjuvant chemotherapy, that is the inaccuracy of the staging.

So what does it mean downstaging on nephroureterectomy specimen when our clinical staging is not so accurate on CT, as we know? There is also the potential risk of delaying nephroureterectomy. And this complete response rate, particularly if we don't use cisplatin, if we use carboplatin, the complete response rate with neoadjuvant chemotherapy is below 3, 5%. So it's nearing zero. Obviously, the advantage of neoadjuvant chemotherapy is that the patients have a better kidney function before nephroureterectomy. As adjuvant treatment, we know that the POUT trial actually set the cisplatin as a standard of care for patients with locally advanced UTUC after nephroureterectomy, and there's been a 55% reduction in the disease, improvement in the disease-free survival. Unfortunately, the drawback is that many patients, particularly elderly, are actually unfit for cisplatin. And, again, carboplatin, we don't really know how much is working.

So the question is, what should we do in patients who actually have a poor kidney function after nephroureterectomy? There has been an attempt to look for checkpoint inhibitors. For instance, there is a large randomized trial assessing the role of nivolumab in a large series of urothelial cancer. It actually was a positive trial because there was a doubling of the disease-free survival in the overall population. But if we look at the [inaudible] group of 150 patients who had UTUC, actually, well, you can see that probably it's less clear whether there is an advantage by using adjuvant nivolumab. So I think that also in this field, there is still some work in progress and the jury is still out whether checkpoint inhibitors could be employed as adjuvant treatment. I think that's it because I would like now to have a discussion with you, Sam.

Sam Chang: Paolo, thank you so much. I think those three areas you hit upon are really the ones that I think have always garnered the most interest. Let's start with the neoadjuvant versus the adjuvant because you laid out clearly the concerns of each and the advantages of each. Within your institution, are there certain patients or characteristics that lead you to choose neoadjuvant, or as your group, do you tend to follow the level one evidence and just do adjuvant? For us, bigger, larger tumors, areas of concern perhaps of nodal disease close by, but no clear evidence of metastatic disease. We tend to do neoadjuvant, especially if their renal function we think would definitely worsen. I was wondering what the kind of usual plan is and algorithm that you and your institution follow.

Paolo Gontero: Well, thank you very much for your question. I must admit that neoadjuvant chemotherapy is not very common, in general, in Italy, and it is not the same in my institution. I already pointed out that, unfortunately, nephroureterectomy, lower down, the rate of patients that are fit for having some kind of perioperative chemotherapy, particularly when it's cisplatin-based. And so, if we have 50% of patients preoperative that could be fit postoperative sometimes in our set of patients, particularly those who are elderly, they drop down to around 20%, which is really, really quite miserable. There is another point is that many patients, they present with hematuria, which we know is, unfortunately, a difficult to treat hematuria when they have an upper tract tumor, locally advanced. And this is another point that prevents us from having the possibility for neoadjuvant treatment.

Paolo Gontero: Personally, what I really like very much, in this case, is the locally advanced with the [inaudible] disease. If the patient is a cisplatin fit, this is the ideal candidate for neoadjuvant treatment. And we do have some kind of retrospective evidence showing that actually there is some kind of response. It's not really a dramatic response. The complete response rate, as I pointed out, is not very high. But I think this is definitely the subset of locally advanced disease, obviously, non-extranode metastatic that we consider for neoadjuvant chemotherapy.

Sam Chang: Yeah, I agree with you. I agree with you totally. In terms of risk stratification, you know, I love the fact that the EAU was attempting to differentiate treatment based upon risk factors, and you showed the low and the high risk and this newer kind of intermediate risk. As you evaluate patients, can you tell me your three most important variables, just for you personally, that help dictate on how you choose conservative versus a radical nephroureterectomy. And they could be very different. You could say, well, renal function is the most important. But what are the few factors really important to you?

Paolo Gontero: Yeah, this is absolutely a very appropriate question. Well, I think that the most important of all is, in my opinion, is the appearance on CT and the biopsy, the grading on biopsy. If we have a high-grade biopsy, or those cases with a positive high-grade cytology and the appearance on CT, these are probably the most crucial variables. Well, you could question hydronephrosis, it's true. But if you have a low-grade tumor in the ureter, you can have hydronephrosis, and this does not necessarily mean that the tumor is invasive.

The same for size. I mean, two centimeter size, I know the NCCN, they use guidelines. They use 1.5 centimeter. That's just related on the location of the tumor, on the fact that is multifocal and sometimes you can just see on the CT or ureteroscopy, obviously. But sizing itself cannot be represent a limitation. And sometimes, as you pointed out, patients with imperative indications, [inaudible] with a solitary kidney, with a baseline chronic renal failure, those really you attempt to do conservative treatment. You just don't bother too much about size because the limitation of size is when the tumor, for instance, is low grade, it's just a matter of technology. If you have good technology and the tumor has a location that is approachable, I think the size itself cannot be a limitation.

Sam Chang: Yeah. I couldn't agree with you more. It's almost an artificial, I think, when the NCCN have made these numbers. Time to diagnosis, all those things matter. And, to me, your point of low grade versus high grade, I think is essential. So last question, and probably the most difficult one is, what are we going to do with these people who may have Lynch? Let's focus, because I don't know what to do with these patients that have Lynch syndrome, or at least genetic changes. They may not have even had initial colorectal carcinoma or an endometrial, but we think they've got, or we know they've got mutational changes. How do you screen? Is it yearly, just urinalysis? Is it upper tract disease? Is it cystos every year? How do you screen? Because I tell you, I don't have one set policy. If they already have a cancer, I'm much more active in terms of their screening. If they have a strong family history, I tend to do less. But I'd be interested to hear what you said.

Paolo Gontero: Well, I think you pointed out quite a hot topic. Well, honestly, I must tell you that, at least in my country, but also in Europe, even the medical history to detect those cases with Lynch syndrome is almost overlooked. And actually, the recommendation, as I pointed out, is weak. And so when a recommendation is weak means that you are not bound as a clinician to go in depth. When we come across a patient who has Lynch syndrome, yes, this is even more difficult. I agree with you. How should we screen for the spectrum of Lynch syndrome cancers? Certainly, I think that personally, this kind of patients would deserve to be placed in a special clinic, which is not necessarily a urological clinic, obviously, and meaning that there must be a protocol that has to take into account the most important, the strongest risk for any cancer.

And talking UTUC, how do we screen? Obviously, we know that as a screening for our side, well, ultrasound is certainly and urine cytology are probably the most, let's say, common type of investigations that can be done. But we know that urine cytology is suboptimal to detect high-grade atypias, and ultrasound cannot pick up all the upper tract tumors. I think that in this respect we have new molecular marker that are coming on the market that looks to be promising, and some of them are being investigated also for upper tract tumors with interesting results. Unfortunately, these marker have a very, very high negative predictive value. They are mostly used in the follow-up of non-muscle invasive bladder cancer. Their diagnostic power is not being assessed thoroughly from this point of view, but I think that this could be a strategy to have a highly sensitive urine marker for the follow-up. It could be the winning strategy for patients with the Lynch syndrome.

Sam Chang: Yeah. Paolo, two great, I think, excellent points. One is the referral to some type of genetic screening clinic. That's one of the biggest areas of need in terms of demand and lack of actually skilled providers in the US, that a wait for our genetics hereditary clinic when it comes to hereditary cancers, is months and months because we don't have a lot of genetic counselors or enough skilled in setting up algorithms and protocols, like you said. And then the second point with the screening is the whole balance of, yeah, we can do cystoscopies and CT urograms on everybody every three months and we'll catch them early. But we can't screen everybody with all those things. And then the more less invasive screenings, just as you said, ultrasound and cytology, they don't necessarily pick up everything. But the goal of, I agree totally, with these urinary biomarkers to be able to give a urine sample, run a test and be able to be diagnostic, I think is, and a lot of studies going into it. It's quite exciting. Paolo, thank you so much. We really appreciate it-

Paolo Gontero: Thank you.

Sam Chang: Here, and always good to see you virtually. I want see you again in person soon, I hope. The very best to you. And again, thanks, sir, so much for your time and your expertise.

Paolo Gontero: Thank you. Thank you very much, Sam. Thank you.