Alicia Morgans: Hi, I am delighted to have here with me today, Dr. Kala Sridhar, who is an Associate Professor of Medicine at the University of Toronto and a GU Medical Oncologist at the Princess Margaret in Toronto in Canada. So lovely to have you here with us today.

Kala Sridhar: Thanks for having me, Alicia.

Alicia Morgans: Wonderful. So I love your take on urothelial cancer, whether it's upper tract or bladder. And really, you have such a wonderful way of putting all of the lessons that we've learned in bladder cancer and in urothelial cancer into context.

At GU ASCO this year, you were a wonderful asset in your ability to host a series of complex and controversial cases in urothelial cancer. And I'd love to review those with you now and just pick your brain about how you thought through those cases.

Kala Sridhar: Sure.

Alicia Morgans: So why don't you get us started. Let us know about... If you had a patient, for example, and this was one of the cases that you discussed, who had muscle-invasive bladder cancer and who had clinical node positivity. Things have actually changed in the last year or certainly in the last iteration of the AJCC manual for this patient population. How did you and the and the team on the stage discuss thinking about patients who were clinically previously considered metastatic by nodes?

Kala Sridhar: Right. So I mean, you're right. There has been a change, a shift in how we categorize or classify these patients. In the past, the thinking was you are node-positive, that's it. You are metastatic. And there wasn't a lot of thought given to local be it cystectomy or bladder-sparing approaches.

With the change in the AJCC, patients with node-positive disease may still be considered salvageable in terms of local treatment. You can still do a cystectomy potentially. You could still do bladder sparing, and some of these patients are getting cured. So I think that's an important consideration.

So we discussed what the implications are of the change in the staging. And the other thing that... The important thing that came into this discussion was how does that change impact on what we do? So in the past when patients had node-positive disease from the point of view of neoadjuvant chemotherapy, we would usually give six cycles of neoadjuvant platinum-based chemotherapy.

So with the change in the staging and these patients are now being considered for local modality treatment, you're asking the question of do you do four cycles or six cycles? In the traditional advent setting, we would usually give four cycles as you know, in the metastatic setting, we would give six cycles. So now as these patients are being reclassified, now do we do four or do we do six? Right? So that's, that's an important question.

In my practice, I find mostly I do four and I try for more, but I don't always get there. Right? So patients often just get too frail or just can't handle more than that. We just did our Canadian guidelines and we sort of put it somewhere between four and six. You try to aim for four at least. You can push to six if you can, depending on the patient.

In terms of the regimen, those stay the same either gem-cis or dose-dense MVAC. There's not a lot of data necessarily in the neoadjuvant setting. Much of that has been extrapolated from the metastatic setting as you know. But I think that the idea there being that in patients with node-positive muscle-invasive urothelial cancer, you give four to six cycles of neoadjuvant chemotherapy followed by some type of local modality treatment; be it either surgery or bladder preservation. So that's what we discussed really in the first case.

The other interesting component and perhaps an evolving area is the concept of radiation therapy. Can radiation therapy be given to patients with positive margins to maybe enhance local control? That's something that we often haven't done because we worried about the small bowel falling into the pelvis and that type of thing. But with newer, more modern techniques, I think it's opening the door for that, especially in a setting of margin positivity where there's a high risk of local recurrence and this disease is not so nice when it recurs locally.

Alicia Morgans: No, no it's not. And just to comment on the chemotherapy approach for these clinically node-positive patients. It's interesting that that question... And at this point I'm actually doing the same thing, trying to get four to six cycles of neoadjuvant chemotherapy in. Often we're going to cystectomy, but actually there are many patients who say after that chemotherapy, I would like a bladder preservation approach.

Kala Sridhar: Right.

Alicia Morgans: If you're doing that, do you switch? So when you're doing bladder preservation often, and we'll get into this in more detail in later cases, but there are three main regimens that we typically use in terms of bladder preservation. The ones I use at least are weekly cisplatin, 5FU, and mitomycin; and then there's a twice-weekly gem and often this is delivered over a six week period with radiation.

Kala Sridhar: Right.

Alicia Morgans: If you have used say dose-dense MVAC or gem-cis, you are using some of the agents that you might be using in the combination in terms of the chemoradiation section.

Kala Sridhar: Right.

Alicia Morgans: Are you switching your agent or what are you doing when you're then going to chemosensitization for radiation?

Kala Sridhar: That's a really good question. So we've published on this recently, just looking at our sort of series of patients we've treated, we tend to go to single-agent platinum as a radiation sensitizer, usually weekly for six weeks during the duration of radiation. Sometimes we're finding patients are getting between four and six cycles of the concurrent treatment with cisplatin.

In patients who are frailer or maybe can't get cisplatin or have issues with renal function, I will often do gemcitabine and sometimes I would do it weekly... Once weekly instead of twice weekly as you mentioned; and that also is a very well-tolerated regimen.

And third, what's interesting is sometimes my radiation oncologist will say, "Well, you've achieved a PCR, a pathological complete response with your neoadjuvant chemo. You know, a weekly dose of concurrent chemo that you miss may not really be that big a deal." So that's how we're doing it, but we did find it was feasible to do it; to give neoadjuvant followed by concurrent chemoradiation.

You're right, the three regimens are potentially available. I don't use a lot of the mitomycin/5FU just because sometimes it involves getting a line and by the time we get the line they are halfway through the radiation.

Alicia Morgans: And that can be challenging.

Kala Sridhar: Yeah.

Alicia Morgans: And just to put one more comment out for the node-positive patients, the ECOG Cooperative Group actually has, and hopefully it will open in Canada when it does open ...

Kala Sridhar: Right.

Alicia Morgans: ... But in development and I think through perhaps protocol development already at this point, a study for chemo/radiation bladder preservation after four to six cycles of neoadjuvant chemotherapy in clinically node-positive patients. There actually is, I believe, an IO, maybe atezolizumab as well included in that whole construct.

It is an area of actively evolving interest and progress. Patients who want to be involved I think really will have an opportunity to engage in clinical trials or perhaps just get this through the standard of care.

Kala Sridhar: Oh yeah, for sure. So even at our presentation today, we showed four, and that's not an exhaustive list, of course, trials in this space that are looking at the introduction of immunotherapy into this setting and it was interesting that each of the trials was somewhat unique, meaning some of them allowed for neoadjuvant chemotherapy, some of them had only concurrent chemoradiation and added in the IO into that setting. And then some had an adjuvant strategy where you don't get any IO except after the concurrent chemoradiation is all done.

So I think they're all going to answer a uniquely different question. And I think ultimately if a patient can retain their bladder, I mean they only have their own bladder, I think it's a huge benefit for patients instead of this thought that automatically they're going to lose their bladder.

Alicia Morgans: Well let's focus on that. We did our clinically node-positive patient population, thinking about a neoadjuvant chemotherapy approach and then surgery or chemoradiation to consolidate that response. And then if you do consolidate that response with surgery, thinking about potentially adjuvant radiation if you have positive margins. But what about chemoradiation as the primary planned modality, clinically node-positive or not.

Kala Sridhar: Yeah.

Alicia Morgans: Tell me your thoughts on chemoradiation.

Kala Sridhar: I mean I think it's actually a very well-tolerated treatment. If you remember at the outset, we talked about the patient population, the group that was originally getting this were often old and frail and sometimes quite unwell but were able to tolerate this approach. So that is very encouraging. So when you now move it into a healthier or fit patient population, they don't have a lot of trouble with it.

We showed actually at the session today that although the FACT scores go down briefly while they're on their treatment, which one would expect after they come back up to normal levels. And so I think that's a really important thing because there's a lot of morbidity and mortality associated with a cystectomy and a patient having a bag. There's body image issues, all sorts of things. So if there's a way that we can safely avoid that, I think we should try.

I think the important thing though is these patients do need to be surveyed. After they've had their bladder sparing, they need to be monitored closely. So we at our institution do CT scans every four months and they get cystoscopies every three months.

If when they get the cysto, if they have a non-muscle invasive recurrence, they are treated as a non-muscle invasive. They have a TURBT plus or minus BCG. But if they have a muscle-invasive recurrence, at that point then they must get a cystectomy.

So that's how it sort of plays out. But I think it's an area that really, really we need to look into because I think it offers so much for patients potentially.

Alicia Morgans: I completely agree.

Kala Sridhar: Yeah.

Alicia Morgans: And then sort of focus on our final group where we have advances and controversies, upper tract disease. The POUT data is finally on its way to us in manuscript form. I hear it's on its way. Can you remind us what POUT was?

Kala Sridhar: Yes. So POUT was a study that was really looking at the upper tract urothelial cancer and it really randomized patients to surveillance or to adjuvant therapy. And that could be either cisplatin or carboplatin-based in the adjuvant setting. Essentially it showed a very encouraging benefit to giving chemotherapy in the adjuvant setting.

Not surprisingly, as I tell my patients, the upper tract is a thin wall, like a straw. And so it's very easy for those cancer cells to get up, right? So the goal is to give some form of treatment to go after the micrometastases.

And so I guess the question... This study compared to adjuvant versus nothing and showed a benefit to adjuvant, but it didn't compare adjuvant to neoadjuvant. And so we don't have data, we are in a sort of data-sparse area if you will.

And so I think that's a really important question that we need to address. Remembering of course that in bladder, in muscle-invasive bladder, neoadjuvant is the accepted standard.

Alicia Morgans: Yeah.

Kala Sridhar: So in upper tract, one of the advantages of a neoadjuvant strategy perhaps a few advantages, but one for sure is when patients have a nephroureterectomy, often what happens is their renal function will decline. So you're not able to necessarily give the cisplatin at the doses that you'd like to. So that's one of the concerns.

On the other hand, you could argue that an adjuvant strategy is good because then you have all the pathological staging. When you look at the forest plots on the POUT study, really there's not a big difference between cisplatin and carbo, so maybe it's okay. There's a lot of discussion around that going on.

In my practice, I tend to try to give neoadjuvant wherever possible. It is somewhat gratifying to see the cancers shrink, to see that. And I find my patients tolerate neoadjuvant better than in the post-op setting when they are dealing not only with being post-op but now getting chemotherapy as well.

So for those reasons, I tend to favor a neoadjuvant strategy. I think it's really an open question but it's really nice. Dr. Birtle and colleagues really need to be commended for getting this trial done. It's a very difficult space, a lot of preconceived notions about what we should or shouldn't be doing. But they got the trial done and I think it was it was a first of its kind and I'm thrilled that it will be published in the Lancet. It's been accepted for publication.

Alicia Morgans: Wonderful.

Kala Sridhar: We just heard that today. So I think it's great news but I think it really speaks to that issue of what do we do in upper tract disease? We know it's high-risk.

Alicia Morgans: Absolutely. And the answer is we do chemotherapy, whether it is before or after surgery, we do chemotherapy.

Kala Sridhar: Right.

Alicia Morgans: So I sincerely appreciate you again sharing your very important, clinically relevant expertise. Thank you for going through these controversial issues and updating us on everything from AJCC staging to chemotherapy in upper tract disease, all the way to bladder sparing and where we're going there. I just really appreciate your time.

Kala Sridhar: Thank you for having me.

Alicia Morgans: Yeah.