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Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology in Houston, Texas. And I'm joined today by two experts from Europe. I mean, we have Professor Alison Birtle from the UK and Professor Morgan Rouprêt from France. Welcome, both of you.

Alison Birtle: Thank you very much. It's lovely to be here.

Ashish Kamat: So we had this really exciting debate at the EAU earlier this year that the two of you participated in on the pros and cons and the timing of therapy in patients with upper tract disease when we're considering neoadjuvant versus adjuvant therapy for patients, which is a really interesting topic because we have some data and we, of course, have level 1 evidence, but then we have the practicalities of what happens in the real world. So with that in mind, Alison, since you led the POUT study, let me have you maybe just summarize the findings of your study for our audience.

Alison Birtle: Oh, thank you very much. So the POUT study was run across the UK in 75 centers. It was a very pragmatic study looking at patients who had already had a radical nephroureterectomy and had completely resected T2 to T4a, N0 to N3 upper urinary tract carcinoma. They had to have a negative scan within 70 days of their surgery and then start either a surveillance period or be randomized to four cycles of adjuvant chemotherapy. And that could be GemCis or GemCarbo.

And it was very pragmatic. But we were quite stringent about the reasons for using carboplatin was only for GFR alone. So if your GFR was between 30 and 49 you got carboplatin. And if it was above that, you got cisplatin. And the primary endpoint of the study was disease-free survival, initially planned for three years. And that was because if you have an adjuvant study, you would need so many more patients if you had overall survival as a primary endpoint. So we had OS as a secondary endpoint.

So the study shut early not because of any safety concerns, but actually because we met the endpoint at two years rather than three years. So that was presented in 2018. And then we've had follow-up data with the long-term follow up since then, which has shown an improvement in disease-free survival, and event-free survival, and metastasis-free survival, maintained at three and five years of around 17% for DFS and 14% for metastasis-free survival across all subgroups.

And in fact, the updated data that were published last year in JCO actually showed that the confidence intervals for the carboplatin arm had narrowed, which actually strengthened the carboplatin argument as well because there were originally some criticisms about the carboplatin.

We're just writing the surgical paper at the moment. A radical nephroureterectomy without a template dissection was the standard of care because we still are awaiting level 1 data for that surgical intervention, doing a template dissection, it sort of snuck in. And we did do a survey before we even opened the study just to find out what current practice was within the UK. And that's really how we ended up just removing any visible nodes at the time of surgery and then having a negative postoperative CT afterwards.

And so all subgroups benefited from treatments. And we had to stop early because we had met the primary endpoint. So we've done some statistical analysis subsequent to that. And on that statistical analysis, it did meet the OS endpoint, the secondary endpoint.

So it's a study that the UK really got behind. And I have to credit every center who recruited at least one patient and the whole uro-oncology community. But most of all our patients. And two particular men, both of whom have sadly died, Andrew Winterbottom and Chris Harris, who were our patient representatives on the study.

Ashish Kamat: Thanks so much, Alison, for that succinct summary. And of course, we recognize the contribution of patients to everything that we do, which is why we do all that we do. Morgan, if I could ask you, clearly, you've participated in these sort of discussions before and it's always interesting to hear your perspective. So if you could just take the contrary approach and tell us your, number 1, thoughts on the POUT study, and 2, how does it fit in into your practice when you are counseling a patient with upper tract disease?

Morgan Rouprêt: Yeah, no, thank you. I think the study had a massive impact, and it was a game changer in the field, and was immediately incorporated into the guidelines. It was the first time ever we are fighting to say, look, there is bladder cancer, there is upper tract tumor and these are distinct entities and we need to have good level of evidence that is going to stick uniquely to upper tract.

And Alison Birtle, and her team, and all NHS and what they have done in the country was fantastic because it was a trial which was not industry-driven but academically done to assess a very good question. But the reality is that the median age of this patient is 75 years old and we are in a situation where we take out a kidney. And so we are not always in a situation in the postoperative setting, which is, I would say, optimal to deliver a cisplatin-based chemotherapy.

This is the reason why the other way around is to see the possibility to deliver the treatment in a neoadjuvant setting, as we do it in muscle invasive bladder cancer. The reality is we want to be very pragmatic, as Alison mentioned, is that delivering systemic treatment needs to assess the reality of the tumor, and having a good TURBT in the bladder is a reality.

Bringing back a biopsy in the upper tract is not always easy. So most of the time, the trials that have assessed the possibility to deliver a neoadjuvant treatment, we have done one phase II in France very recently, which was presented at ASCO GU with Nadine Houédé, durvalumab value plus chemo.

It was on, I would say, composite criteria based on the imaging. But the reality if you want to-- let's say you have FDA or EMA approval for that, I don't know any medical oncologist would be happy to deliver a treatment without the proof, the historical status, and the evidence of the existence of the cancer. So neoadjuvant, why not? But it appears to be difficult in upper tract. It can be tricky. It can be tricky.

Ashish Kamat: You raise an excellent point there, Morgan. And of course, as both of you are aware, there are several groups, including the East Coast at Memorial and here at M.D. Anderson, where we use certain criteria, the grade of the biopsy, the imaging findings, all of these composite factors to try to predict who might get upstaged at surgery and then maybe offer them neoadjuvant therapy if it looks like after the nephroureterectomy they would drop their GFR, not be candidates. Alison, as an oncologist who clearly has the patient interest in mind, how does that paradigm fit in with what your trial obviously showed, but also your actual counseling of patients?

Alison Birtle: So I mean, even in the best of hands, we've had some of our wonderful colleagues who've developed these prognostic nomograms in putting together hydronephrosis and cytology and what it looks like. But even the best of hands, that sensitivity and specificity isn't 100%. And that is the problem because you look at the cause-specific survival for pT1 upper tract tumors and it's very good.

So we don't want to overtreat somebody with systemic treatment of any form, which can come with life-changing or even completely life affecting by death side effects if we don't need to. And in fact, when we did the POUT study, the commonest reason for ineligibility was that the patient had been thought to have a T2 or above tumor beforehand. But then when we got the path back, it was pT1. So we'd have overtreated those patients whose five-year DSS is actually significantly better than those with T2.

And I think the issue about-- I do think the issue on renal function has been overstated. Because if we look at drops in GFR, then you can get carboplatin in, for many of these patients can get cisplatin in. But the Galsky criteria with a GFR of above 60 has never really been used in the real world other than for patients in clinical studies.

And 20 years of being a consultant, I've always treated down to GFR of 50 or 45 using fractionated cisplatin. And you can manage to do that for the vast majority of patients. So I think the GFR thing has been overrated, to be honest. I apologize, my cat is so excited by upper tract tumors that he's joining in the discussion.

But I do think Morgan is very right. Oncologists, we're simple souls. We like to have a bit of paper that says this is a cancer that we need to treat with systemic treatment because we don't want to over treat somebody whose prognosis is very good and potentially give them a life-limiting toxicity.

So a grade 2 peripheral neuropathy with cisplatin, for example, because we're giving high dose cisplatin, that's going to affect your ability to do the simple things in life that we all enjoy, like doom scrolling on our phone, for example. So I think we just have to be very mindful that we're not overtreating some patients where we don't have that certainty.

And if we look at all of the studies we've done in UTUC, where we thought there was a definite upper tract tumor, there's a high rate of non-upper tract malignancy and sometimes, a high rate of non-malignancy. So even in Morgan's fantastic iNDUCT study, I think there was one patient with an RCC in that where they thought it was going to be UTUC.

Tim O'Brien's ODMIT C study, single-shot mitomycin, more than 10% of patients either had the wrong type of cancer or no cancer at all. So we don't want to be giving the wrong treatment to the wrong type of cancer or overtreatment where we don't think that you-- where we think it might be a pT1 tumor.

And there's always this mismatch between the patients who are having downstaging chemotherapy and neoadjuvant. And people often mix it up. So if you've got a big, big bulky tumor that you're not going to be able to operate on without worrying about leaving something behind, that's clearly not neoadjuvant treatment. That's downstaging. And that's why some of the reviews on "neoadjuvant treatment," because they include all comers, they're very murky, as our guidelines group found out because we published a systematic review on the node-positive patients at the beginning of the year.

Morgan Rouprêt: Alison and Ashish, I think one good way maybe to skip the debate of neoadjuvant and adjuvant, the most logical thing in the upper tract would probably be to go and to deliver when you have the specimen and to discuss the treatment when you have the specimen because the quality of the assessment is 100% you have the guarantee that you have the good assessment.

And so taking into account the environment which is changing in these tumors and we have no evidence in metastatic urothelial carcinoma that pembro EV probably is going to change the way we treat these patients, we will skip probably the debate around the renal function, or let's say we are not in a world where one size fits all.

But it is true, I see probably, that there will be a subgroup or a big group of these patients that are likely to be suitable for pembro EV for the next future. And I would be happy to go back to the adjuvant setting, which is the most logical one, I think, in that particular situation.

Ashish Kamat: Yeah, that's a great point that you raised, Morgan. And I was going to bring that up because, obviously, things are changing. So Alison raised an excellent point about the GFR. And if you look at the NIAGARA study, which kudos to them for including patients down to 40 GFR and allowing cisplatin-based therapy, which clearly is something that we do in academic centers but people sometimes need to know how to do that in other places where they're dealing with multiple cancers.

In the interest of time, obviously, because we could go on forever, but let me flip back to you, Morgan, a little bit, because Alison raised some good points. I thought her cat was coming in there because she was talking about CAT scans.

But for the trainees that are listening to this, because clearly, there are people at all levels listening to this debate, how would you optimally stage and work up a patient that you're considering for, say, nephrou followed by, say, adjuvant therapy with Professor Birtle. What's your staging workup for these patients? Are you now saying, I'm just going to take out the kidney because I'm going to give adjuvant therapy? Or are you still doing your attempt at a biopsy to find the histology, et cetera?

Morgan Rouprêt: The biopsy goes into the direction where I think that there is room for kidney sparing strategy. If I feel that the patient is suitable for radical nephroureterectomy outside the clinical trial, I would follow the POUT trial. I do the surgery. I go back to the tumor board with a specimen, with a pathological assessment, and then I discuss with the oncologist systematically.

This is the way I do in 2025. We had and we were running the enrolling patient in the phase II iNDUCT trial that Alison was speaking about. And so outside the clinical trial, I follow the path. But I'm really curious to see how the pembro EV or let's say, any other systemic drug is going to impact and influence the way we treat upper tract within the next few years because I'm sure we will have to be flexible and it will be incorporated into our practice.

Ashish Kamat: Thanks. And, Alison, closing thoughts from you?

Alison Birtle: Oh, I'm really all about circulating tumor cells and ctDNA at the moment. And having just seen the data on NIAGARA in muscle invasive bladder cancer and looking at the survival rates of patients whose ctDNA cleared with neoadjuvant treatment and looking at the data we've got from IMvigor011, giving adjuvant atezolizumab or placebo to patients whose CTCs weren't positive but we got the data from the CTC negative arm.

And if it stayed negative, it doesn't matter whether you've got high risk disease or not, after your cystectomy, you still do very well in the long term if your CTCs remain negative. And I want to do that-- I want to see that in upper tract. And I think that is going to really drive forward who we treat on a much more personalized basis. And of course, we've got the FGFR biomarker as well and bringing erdafitinib forward earlier in the pathway for the patients who are biomarker positive.

So I think it's quite exciting at the moment. But I'm really all about CTCs. I haven't been quite this excited about something for a while, since I got my cat, to be honest.

Ashish Kamat: No, I think ctDNA might provide us with the ability to tailor and personalize therapy. Obviously in the upper tract, it hasn't really been studied, so we need to assess that there. But in the bladder cancer world, it really is changing how we look at adjuvant therapies. With the two of you on this conference and Zoom call, I could talk forever. But I am looking at the timer and we're running up on time. So I just want to thank you both for taking the time. Always a pleasure.

Alison Birtle: Oh, you're very welcome. Lovely to see you.

Morgan Rouprêt: Thank you.