Managing High-Risk NMIBC
Transcript: Selecting the right treatment approach
Fred Witjes, MD, PhD, and Ashish Kamat, MD, MBBS, FACS
Podcast recorded August 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
- [Ashish] Hello, everybody, and welcome to "Expert Voices: "Navigating Non-Muscle Invasive Bladder Cancer." I'm Ashish Kamat, urologic oncologist and I'm delighted to welcome a dear friend, a partner-in-crime, someone who's collaborated with us in many, many decades on all things bladder cancer, Professor Fred Witjes. Professor Fred Witjes is a global expert neurologic oncology, and he's sort of the perfect person to talk about today's episode, which is the right approach for the right patient and the importance of integrating multidisciplinary care early on. So Fred, let's dive right in, right? When do you opt for the nuances of intravesical chemotherapy right after TURBT for a particular patient?
- [Prof. Fred] Well, Ashish, obviously depends on the patient and on the final pathology on the tumour. With regard to the patients, there're not that many issues that might force me to choose for something or to delete something. If somebody has an alert mitomycin C for example, of course you're not gonna do that. And if you are considering one instillation after the operation with a patient with a low-risk tumour, obviously you should be very sure that there was no perforation because then you are doing something very dangerous, you might give chemotherapy in the abdomen of the patient, obviously that's something you don't wanna do. And then, of course, the rest of the, let's say the instillation schedule depends a bit on what you already see during the operation, if you think it's a, for example, high-risk patient, meaning for example in a T1 or CIS, I wouldn't give one instillation. That's not very useful because you're gonna give something else, BCG or chemotherapy anyway. And if you think it's a very small low-risk tumour and you don't have perforation obviously, you might consider one immediate instillation after the operation if logistics allow you to do that. And I know that's a little bit different in, for example, UK or in the Netherlands or in the US, but basically if you follow the guidelines, you should give in a low-risk patients mediate instillation. So it depends on some patient factors, your TOR, and obviously what you see or expect from the final pathology. And of course, if you have your final pathology, you will adapt what you're gonna do. - [Ashish] Yeah, so you raise some important points, Fred. You know, there's a lot of data out there that suggests that patients with higher risk disease don't do as well with early intravesical chemotherapy. My belief is that it's because it delays the inevitable, I don't think the chemo makes the cancer worse. What's your thought there and and how do you guide people?
- [Prof. Fred] Well, I don't think it makes the cancer worse and you're not gonna delay a lot. But we've looked at that, you know, longer time ago with EORTC studies and we've seen that if you're going to give additional instillations anyway, whether it is chemotherapy in intermediate risk or BCG in intermediate or high risk, the additional advantage of one instillation, of course, is very, very limited. And you have to realise that if you give one instillation after the operation, there is still small risk that there is a perforation which you didn't see, or you will get some cystitis for the patient. So it's not very risky to do that. But there are some potential complications that you're not gonna have when you're giving, not giving one instillation. By the way, in the low-risk patients, if you do think you have a perforation, one of the things that I've been doing already for a long time and the rest of literature about that does rinse the bladder for 24 hours with saline.
And again, that depends on your logistics. If the patient goes over the same day, you can't do that. But in my situation, probably the patients will stay overnight and then you can rinse the bladder for 24 hours and that has almost the same effect as one instillation, which does make sense, by the way. - [Ashish] Yeah, no, again, very important point. I think it's a health system issue in the United States, North America for example, it's a very expensive to keep the patients in the hospital overnight, so it's easier. - [Prof. Fred] Sure. - [Ashish] And cheaper to do chemo versus obviously in different systems, salient irrigation can have the same effect as intravesical chemotherapy, very good point there. You talked about BCG, so let's address that a little bit. For patients with high-risk disease, BCG is really the standard of care. Now, how do you select patients that you are gonna recommend BCG to? And let's assume for a moment there's no shortage anywhere.
- [Prof. Fred] So, you know, I've been following guidelines and been chair of the guidelines for a long time. I've been chair of the EORTC bladder cancer group, and there are many, many, let's say risk calculators or risk groups. But I've always taught my residents, if there is a T1 or a grade 3 high-grade or CIS, that's high risk. And you know, you can talk about 20 multiplicity or recurrence rate or all kinds of stuff, the size of the tumour, which I think is very different to measure. So if you will say T1 or high-grade or CIS, that's definitely a high-risk patient. And for me, high-risk patients, like you say, standard of care is BCG. And then if you go to the intermediate risk group, then of course you can choose between BCG and intravesical chemotherapy, I guess intravesical chemotherapy will have a little bit less efficacy, so a higher recurrence rate, maybe even higher progression rate. But of course, it also has some limited side effects less than BCG. On the other hand, if you choose a BCG, you will have a more efficient treatment, more effect, lower recurrence rate, impact on progression. But obviously you'll have some more side effects.
And as you know, of course, our group, the IBCG group made, and we amended that another time some years ago, we looked at some risk factors that can help you in the intermediate risk group to decide between, "Well, it's actually a very low part "of the intermediate risk group "or it's a higher part, "higher risk part of the intermediate risk group." And in the first instance, you might even consider only one instillation. And in the ones that have multiple additional risk factors in the intermediate risk group, I guess you might choose, again, if there's no shortage or whatever, you will probably choose for BCG. And that's what we do in clinical practise. So if it's not too bad, chemotherapy, if your gut feeling says, "Hmm, that's not good," or you can even see that on the risk practise, multiplicity, recurrence rates, size, things like that, you would probably go for BCG. - [Ashish] Yeah, I think the key pearl here is something that you and I, and through the International Bladder Cancer Group, I think the rest of the community has recognised that even though there are risk calculators, et cetera, it's easiest and better for the patient just to consider high-grade, high-risk, use BCG, right?
Don't go with 2.7 centimetres, 3.1 centimetres, all of those things. So I'm glad you mentioned that. Now a lot of our bladder cancer patients are obviously older and many of them frail, and BCG can be hard for those patients, and we'll often hear people say, "Oh, my patient can't tolerate BCG at all." I know you have tricks that you use to allow patients to get the treatment. Could you share some of these tricks that you use in your clinical practise to allow patients to get the induction and maintenance course? - [Prof. Fred] Yeah, sure, and you're right, you know, the average age in the Netherlands for bladder cancer is 70, 74, I think, 73 to 74, meaning, and it's predominantly males, meaning that probably some of those will have lots and large prostate. So one of the easiest things is just to make sure that there is a good bladder emptying. If you think that's not the case, you might give some drugs to help the bladder emptying. Second thing is, if you're gonna give BCG, of course a good preparation and information of the patient surely pays off. You know, I've been working BCG for for 30 years. And as you can see, for example, compared the SWOG study with the EORTC study, there's 10-year difference between those two studies, same schedule. You see that the side effect profile in the SWOG study is higher than in the EORTC study. That's probably experience. We know what to tell the patients, the patients know what to expect. So that's already very important. In my clinic, we have an experienced nurse who does a lot of the work, and they talk to the patient, they make sure that they are going well through the instillation schedule. And then the things that we as a doctor can do is consider if BCG gives too much side effect to give one third dose, which is more or less as effective as full dose.
Although the EORTC study suggested it is a little bit less effective, but the last efficacy is only recurrent rate, so it's not progression. So you still are on the safe side. You can, if you're giving maintenance, then you can stop in the maintenance phase after two instillations instead of three. Also, there is some, some advantage in that, of course you can give painkillers around the instillation, you can give anticoagulating drugs around the instillation. Plus, let's be honest, we are giving the patient the bladder infection because we are putting bacteria in the bladder, so that they have some complaints is obvious. And one of the things that I've been using quite regularly, has been published also, if patients have some problems, I give ofloxacin the evening of the instillation and the next morning it's 200 milligrammes twice or once the evening of the instillation, once the next morning. And that really improves your compliance like one third dose or less instillations.
So there are some tips and tricks which makes you, which makes the patients better in the schedule. It helps compliance, so that's good. - [Ashish] Yeah, and I just again to emphasise, when you said the evening of instillation, it's the evening after instillation, not before because if you do it before, then you can kill the bacteria. So just for the audience to emphasise, it's the evening after instillation. - [Prof. Fred] Absolutely. And my situation, they have the instillation, they go home, we give them a prescription for two tablets or if they need 6 or 12 tablets and in the evening of course they have to drink well, that's of course, don't leave the BCG in for a very long time. One hour really is enough, and then drink a lot. And then in the evening after the instillation, the next morning you get off oxygen. - [Ashish] Now of course, you know BCG is very effective and we've seen in more modern series that it's even more effective now than it used to be before.
And I think it's because of better patient selection, better instrumentation resection. But there are patients for whom BCG does not work, right? And in those patients, the standard treatment for many years has been radical cystectomy. Now we have different options available. It's become a multidisciplinary care because we have systemic drugs, we have intravesical agents. I know many of them are not approved yet in Europe and they're approved in the US. But in general, how do you counsel your patients with high-risk disease that have become BCG unresponsive? - [Prof. Fred] Well, it's actually a very good question. So point one, intravesical chemotherapy, it's not that bad. If you look at the large meta-analysis that Per-Uno Malmström did some 10 years ago, mitomycin is a very effective drug. So even in higher risk, you could consider maybe, you know, if there's a problem with BCG or whatever, you could consider, if it's initial treatment, I don't think in BCG failures, but in initial treatment you could consider a course of mitomycin C, it's not effective, of course, it's less effective for BCG. But some patients do very well on that.
The second thing is that, you know, in so many years of practise, I've become much less aggressive in prostate cancer, but more aggressive in the high-risk non-muscle invasive bladder cancer patients because you know, if they progress they have a very bad prognosis. So you have to be very, very careful. And in that sense, an upfront radical cystectomy in some patients, and maybe we can talk about additional indications for an upfront radical cystectomy, is not always a bad choice. You know, the cysto study that was done by Jim Catto, and he looked at, let's say the quality of life of patients with high-risk and muscle-invasive bladder cancer, who got an upfront radical cystectomy, and those who got all kinds, one in first and second line intravescical therapy and after a year the quality of life of the patients that had radical cystectomy was, to everybody's surprise, better than those who were still running around with a bladder instillation and other things. So again, it's not a bad therapy, of course, it's radical surgery, but you do cure your cancer. And if that's all not being discussed, so if you think it's not a radical surgery and you don't want to give intravesical mitomycin C, I know that there are several options in the US that are acceptable. I think also in Europe, Pembro will probably be used once in a while.
And one of the things that currently I think is used a lot, certainly in the Netherlands and what I hear on the European continent from others is the combination gemcitabine docetaxel. We all have to realise that it's not, how do you call it, on label, or at least it's not really approved for that indication. It's an off-label use of that. But the studies that have been done, and fortunately there are now randomised controlled trials being done compared to BCG or after BCG. But as far as we have seen the results so far, and again it's retrospective and small series, it is really quite effective for patients that, for example, fail after BCG and you don't wanna do a radical cystectomy. And it's a schedule for us as urologists that we know, you know, it's intravascular therapy, and then it's with regard to the side effect profile, initially I thought, you know, giving two in instillations on the same day might be very bothersome for the patient, but it's not that bad, they do very well. And as you know, and that's again, something you don't see a lot, and it's not done in the US a lot, what we use, device-assisted intravesical chemotherapy, and we do very well with that. But that's basically, let's say our personal experience with hyperthermia. - [Ashish] Yeah, no, and as you mentioned, it's good that the patients have choices and we have to keep that in mind.
The gemcitabine docetaxel I've been using now for almost 15 years, and the patients actually tolerated really, really well. Sometimes they ask me, "Are you actually doing anything?" Because they've just come off of BCG. So it's really well tolerated. You know, I just wanna clarify one thing. The cysto trial was done by John Gore, not Jim Catto. It was a North American study. But yeah, that surprised a lot of us because we all thought that patients who have radical cystectomy would have worse quality of life reports, but it was almost, you know, better. And I think a lot of it had to do with the anxiety of having multiple intravesical therapies repeatedly and the appointments, which brings us to a question, Fred, I mean, over the years, and you've been doing this for so long, have you developed certain tricks or tips that you could help the audience understand about counselling patients with radical cystectomy? Because you'll often hear people say that, "Oh, I told my patient "that I said you should have a radical cystectomy "and they refused." And then they come to see you or me and we talk to them, and they're like, "Oh, of course I would do a radical cystectomy. "It was never explained to me like that." So if you could share some of those tips. - [Prof. Fred] Well, of course for you and me, the problem is that all the patients that come to you, me, have already seen 15 urologists, and you know, the fact that they come to you and me is probably because they, in the end, are considering something like radical surgery, at least wanna have an expert opinion on that. I think what helps is, of course, that they realise and see that you have a lot of experience, because again, it's major surgery with even base, there's even mortality. And fortunately we haven't had that for a long time. So I think the fact that you show that you are experienced and that, of course, it's something that helps. We also involve our, sorry, geriatric doctor.
So if the patients are older, they get some advices of those. Our nurses, of course, I always involve the family. I don't speak to only the patient. I always wanna have some family present for additional questions and things like that. And then one of the key issues I guess is like you say, also in the cysto trial, you know, if you leave in the bladder, you one, have, of course, the risk of progression. If you progress, your really miss the window of opportunity because your progression is much, sorry, your prognosis is much worse than if you don't progress. And that's a big difference, a really big difference. So you're playing with fire a little bit. And second thing is if you leave in the bladder, even if you are doing well, and you do maybe radiation or you do again a lot of TORs, your bladder is not getting better. So you will have probably a lot of cystos and you will have intravesical therapy, you might end up with lower urinary tract symptoms.
Whereas if you do a radical surgery, you don't have to get up at night anymore. So it also has some advantages with regard to quality of life. And that's something that you have to explain to the patient. It's not only radical surgery, it also some advantages. - [Ashish] Yeah, and as you rightfully said, it is a multidisciplinary discussion, right? You have to get the geriatric folks involved because you need to get the stoma nurses involved early on, get the patient cleared by medicine, et cetera, et cetera. You know, get all the specialties to really come together. - [Prof. Fred] I always have some patients that other patients can call, you know, patients that already had a cystectomy and have a stoma, females with a neobladder, whatever, I have some of those that are willing to be called by patients that haven't had surgery yet, just to be informed by a patient, because you know, I don't have a neobladder or a stoma. And that also helps a lot for patients to be convinced that it is, you know, it's an acceptable way of treatment. - [Ashish] Absolutely! Fred, this has been a great discussion. You know, talking about the right approach for the right patient, the importance of multidisciplinary care early on. This has been really great, thank you so much. - [Prof. Fred] You are welcome.
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