Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center.

And it's a distinct pleasure to welcome again to this stage, a colleague, a friend, and an expert in the field of bladder cancer, Professor Jørgen Bjerggaard Jensen. Professor Jensen is Professor of Urology at Aarhus University, Chairman of the NUF Urothelial Cancer Group, and he's done a lot of research in publications in urologic oncology. But specifically, Jørgen, we have you here today to talk about your very, very important, I think, for the field of non-muscle invasive bladder cancer, trial that you published the extended results on it recently, which is the Danish Bladder Cancer Study of Chemo Ablation.

So Jørgen, thanks for joining us,

 And take it away.

Jørgen Bjerggaard Jensen: Thank you very much, Ashish, and it's a pleasure to be here. Thank you for the invitation. This is just to share you where I'm located. This is Aarhus University Hospital, and obviously, I'm on the penthouse floor here.

We are here to discuss another view. If you have a patient where you've done a TURBT, the patient maybe had one or two TA low grade tumors, and three to four months later, you see this one. And then, you get a bit annoyed. Why didn't they do some adjuvant installation with chemotherapy for this patient, that might have prevented this recurrence?

Well, the treatment of recurrent tumors, here, you'll go again for resection, and you can do that over and over again and again. Or, you could add mitomycin C as your adjuvant chemotherapy. But do you know whether this works? If the patient does not have a recurrence afterwards, it might be because of the mitomycin, or the patient might not have had the recurrence anyway, and that's a good question to ask yourself, if you want to go into the regimen of maintenance. Was the tumor chemosensitive, or was it just because the patient didn't have a recurrence anymore?

If you look at a very old trial here, but as you can see here, patients undergoing TURBT alone have a higher recurrence risk, compared to patients undergoing adjuvant mitomycin C. But these patients have no recurrence, despite not having administered mitomycin C. So these patients, would it be overtreatment in these patients to administer the adjuvant installation? Whereas, in these patients, it didn't make a difference anyway, because they were obviously not chemosensitive. So in basic, you only have this small proportion of patients who do benefit from the chemotherapy. And you want to select these patients, because they might even benefit from the augmented maintenance strategy.

Can we then select the patients with the chemosensitive tumors? Well, first, we looked at this study from Italy, a pioneering study under the chemo ablation, or neuroactive, and or whatever you call it, where they randomized patients in two groups, between the normal weekly installations or the dose dense.

Very importantly, they found that in the dose dense regimen, 70% of the patients had a complete response, so you could avoid the TURBT. And the next study coming up. This was a multicenter study from UK, the CALIBER study.

Slightly more patients, but a shorter regimen. They only had four installations, and weekly installations, and the complete response rate was lower. So we decided to go for the dose dense regimen when we designed our study, the Danish Bladder Cancer Study number 13, the next trial. This is a flow chart, here you can see the standard on the patients with occurrence. You do as you normally would do, do your TURBT, and then do your adjuvant installations. But we just took this adjuvant installation, the same six installations, and moved them up in the dose dense regimens. And then only did the TURBT if the patient had no response.

We published, a few years ago, our initial results here. Where we could see that our complete response, not as high as in the Italian study, but still, more than 50% of the patients, 57% of the patients, could avoid the initial TURBT here for their recurrent tumors. Whereas, in the other patients, we did the resection afterwards. So more than half of the patients were omitted for the TURBT. We also saw that the side effects for the installations were slightly fewer in the intervention arm, so giving them in an intact bladder meant something.

We just published our follow-up date on this in JCO. Because what would worry you is that, you cannot find any long-term results from the Italian study. And in the UK study, it seems as if the patients with a recurrence still had some active tumor that would grow out.

But very interesting, we found that the risk of having a recurrence was the same in our intervention group as in the control group, where the resection had been done. So it doesn't seem to just be makeup of the tumor. It seems as if, if you have a response to it, the tumor disappears. Especially, if you look at some of the updates that we presented at the EAU conference this summer, where, as you can see here, complete responders, that's the blue line, if they had a complete response, the risk of having a recurrence afterwards was much lower than the patients with no response. So in other words, you could say, if they do not respond to it here, they still have a very high recurrence. Whereas, the complete responses, well, they had a complete response. It's not just makeup that makes the tumor shrink and grow out again. There is actually, a selection of the patients who have the chemosensitive tumors, that you could maybe even higher this recurrence rate to zero by giving maintenance installation.

So in the future, I think we'll still have the primary initial TURBT along for some years, but going for the adjuvant installation in intermediate risk low grade, well you could do another strategy and move it up upfront, and wait to see which patients have a recurrence, and then treat with chemo resection. Because then, you'd select the patients with the chemosensitive tumors, and in the non responses, maybe shift to BCG.

Ashish Kamat: Great. Thank you so much, Jørgen, for going through that in such a succinct manner. If I could ask you a couple questions. And I know you and I have talked about this before, but for our general audience, how exactly do you foresee this being used in the clinic in the real world? Because for example, having patients come to the clinic for chemo ablation in an intensive manner, sometimes it is very hard, for example, in North America, where patients are driving a long distance. So do you recommend selecting some patients for this, or do you use it in everybody at your center now, based on your data?

Jørgen Bjerggaard Jensen: Well, right now we are offering it to all the patients who are fit for it. Or well, you could say, the traveling distance is still the same number of travels to the hospital. And if they have very long to the hospital, it might be a good thing that it's done within two weeks, so they could stay at the nearby hotel or at some relatives or something. But of course, it will increase the travel burden in those two weeks. But in my opinion, I think, a lot of these patients thinks it's an advantage to have it over and done within in the two weeks. Whether you could use the same strategy, just giving it weekly, well, we actually did that when we started it up before the study, and we also saw patients with complete recurrences. It's not as if it doesn't work. So I think you can individualize it, but if the patient's fit for it, I would go for the dose dense, based on the Italian study.

Ashish Kamat: And are you still using mitomycin or any, have you done any studies with other chemotherapies? Any comments there for people that might want to adopt this in their practice?

Jørgen Bjerggaard Jensen: Well, we've only experience with mitomycin. That's the only thing we use as an intravesical chemotherapy in Denmark right now. So that's what's our experience is based on. But basically, in my opinion, I think you could use any kind of installation chemotherapy for this, and of course, get your experience on it. There's no studies in anything else than mitomycin, but looking at the mechanism, you should be able to get the same effect from other chemo therapeutical drugs.

I think the most important thing is, what we learned during the study was that, at first, we looked up in the bladder one month after completing the dose dense regimen, and where we were in doubt whether the tumor has actually been killed or not, we waited one month later. So we found out that the optimal timing for the follow-up cystoscopy is not one month, it's two months, because there, you have more complete responders. And even though it didn't respond at the first month, but first at the second month, you could see it was completely gone, they didn't recur. So it's maybe the process you have there. There might be differences if you go to other chemo therapeutical substances, so you have to get your experience in that, if you try that.

Ashish Kamat: That's a very good important clinical pearl that you just mentioned, because I have used chemo ablation in selected patients. For example, those that have multiple, multiple tumors in the bladder, clearly, you can do TURBTs and you can cauterize, but you're traumatizing a large surface volume. And I use chemo ablation, and when I go back in, because I select out the worst patients, they're not CRs, but there's much less tumors to ablate. But I tend to go back, or go for the TURBT about four weeks after the ablation.

Jørgen Bjerggaard Jensen: Yeah.

Ashish Kamat: And your experience suggests that eight weeks is better. So that's a good clinical pearl.

Jørgen Bjerggaard Jensen: Yeah.

Ashish Kamat: The other question I had to ask is, there's a lot of newer technologies coming up. Where for example, Janssen has a little device where you can put chemotherapy in a stent, and you put it in the bladder, and it releases the chemotherapy over three to four weeks, and you leave it in. Or there's the gel formulation called Jelmyto, which is used for the upper tract, that people are looking at in the bladder. Do you want to maybe hypothesize? Do you think one of those platforms would be ideal for your sort of strategy, where you could put it in the bladder chemotherapy is released over four, five, six weeks, and then you look in?

Jørgen Bjerggaard Jensen: Well, it could be a good idea. I think it's an interesting world we're living in. We have all these different technologies. And even though mitomycin C and BCG are old substances, we can still do very relevant clinical trials with them. And now comes the new devices you're mentioning there.

I think it'll be very interesting to see whether you could increase maybe the complete response rate, or whatever you see in it. Of course, there's also the prices here, because some of the things you're mentioning comes with a price, so you have to weigh that over the maybe more cheap chemotherapy that's out of patent right now. So you could get your experiences in that.

What I would say is, it's a good argument for using the chemo resection instead of the adjuvant installation, is maybe in theory, if you have the tumor there, and you start killing it a bit with your chemotherapy, you might even induce a local immune response to the tumor cells, that you will not have if you have no tumor in there when you give the installation afterwards.

Ashish Kamat: Yeah. And I think that's the basis of some of the bladder preservation studies, where they're using intravesical gemcitabine with systemic IO, to try and augment the response of both. So yeah, I mean, there's absolutely a lot of mechanistic work being going on in that aspect.

Have you done any of those tissue based studies? Do you have any insights you could share with us on that mechanistic aspect?

Jørgen Bjerggaard Jensen: Yeah, we are doing some of the studies right now, and also looking at what influence does different intravesical substances have on the microenvironment with the immune system? So we have a close collaboration with the Lastufka group who is also located here in Norway. We do a lot of research together, where we look at these molecular mass mechanisms, and also these intravesical trials. And we also looked at a different markers that was published from this study in European last year. So we are looking into all these things. At the moment, it's still on the exploratory level, but hopefully, it'll be something we can use in the future to even further select patients for the right treatment upfront.

Ashish Kamat: Yeah. Because you have a special interest in urinary markers as well, right?

Jørgen Bjerggaard Jensen: Yeah.

Ashish Kamat: So, I think that this cohort and all the work you're doing is great in that aspect. Jørgen, we could chat forever, but in the interest of time, let me ask you to close out with maybe a practical sort of how you do it recommendation for people that are listening that might want to adopt this in their practice? Just how do you plan it? How do you do it? When you do the TURBT? Just if you could close with that for our audience?

Jørgen Bjerggaard Jensen: Yeah. Well, we select patients where you'd think that you have multiple tumors, so like you mentioned, cautery may harm a lot of the bladder. So multiple tumors but not too big, so they should be preferably less than one centimeter. And of course, they have to look very harmless. We didn't select patients only with TA low grade. We also include one third of the patients in the trial here, were actually previous TA high grade tumors. So you can do that, but still, you have to get your clinical viewer. But multiple small tumors where you think, "I would still go for the TURBT with adjuvant here. And why didn't I give adjuvant the last time?" There, I would turn it around and give those patients the mitomycin.

If it's a patient who had a TA low grade five years ago, and now have one on two millimeters, I would just cauterize it. So a significant burden, and giving it there makes sense.

Ashish Kamat: And then just to follow up, you'd wait now eight weeks before you go in and assess the bladder. Correct?

Jørgen Bjerggaard Jensen: Yeah. Yeah, we do that.

Ashish Kamat: And have you found any unusual aspects of the TURBT, any precautions people need to take after chemotherapy? I personally haven't found any difference in hemostasis or anything, but have you, with your large experience, found anything different?

Jørgen Bjerggaard Jensen: No. No, no, not at that point. We saw some of the patient who had very big, it almost looked necrotic in the bladder, but that was patients in the control arm, where they had the adjuvant mitomycin after the TURBT. Where we saw in the worst bladders, that's probably just coincidental. Sometimes you have these patients that look very peculiar during the installation. You might experience that also in the chemo ablation, but in our experience, not more frequently than normal. So I'd say, for your TURBT, you don't have to take any precautions.

One interesting thing was though, that the number of patients where we could just do the procedure in the outpatient clinic, with biopsy and calculation, was much higher in the patients in the intervention arm, even though they didn't have a complete recurrence. So you can go from needing to have the patient anesthetized and doing your resection, to more outpatient procedures also based on this, even in the patients that presumably have no complete response.

Ashish Kamat: And Jørgen, in the patients that have a complete response when you assess them, you obviously don't do a TURBT or biopsies. But you follow them at the normal schedule after three more months, correct? Or do you automatically go much longer?

Jørgen Bjerggaard Jensen: In the study setting, we followed them close, like it had been a high grade tumor in that arm if they had a complete response, just for safety. But right now we have changed that, so we'll just follow them as if they had had a TURBT, so after three, four months, and then we'll increase the periods.

Ashish Kamat: And in your real world practical experience, if a patient has had a CR with the chemo ablation, and then say, recurs in nine months or so, would you recommend chemo ablation again to that patient? Or would you say, "Well, now let's go to TURBT and then do adjuvant therapy."?

Jørgen Bjerggaard Jensen: That's a very good question. Fortunately, we haven't had a lot of these patients. As you could see, the recurrence risk is very low in those patients. We are doing a follow-up study to see what the best regimen is in those patients. I have tended to do the calculation, then if they have a recurrence again, I tend to give them BCG. But you could probably repeat it. I'll say, if it's within a year, I would probably shift to BCG. But if it's after two years, I'd definitely go for the chemo ablation again.

Ashish Kamat: Great. Once again, thank you so much for taking time off from your busy schedule. It's really important to get these little clinical portals out to our listeners, so thank you so much. And good to see you, as always.

Jørgen Bjerggaard Jensen: Yeah, likewise. It was my pleasure, Ashish. Thank you.