Managing High-Risk NMIBC
Transcript: NMIBC: Surveillance and follow-up
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.
- [Interviewer] Hello, everybody and welcome to Expert Voices: Navigating non-muscle invasive bladder cancer. I'm Ashish Kamat, neurologic oncologist in Houston, Texas, and I'm delighted to be joined by Professor Fred Witjes, who really needs no introduction. Global expert, a dear friend, part of IBCG, part of multiple guideline panels, really well entrenched in bladder cancer. And Fred is joining us today for the episode titled: "Surveillance and follow up in intermediate risk non-muscle invasive bladder cancer". So welcome, Fred. - [Fred] Oh, thank you very much, Ashish. - [Interviewer] So, you know, intermediate risk bladder cancer is something that we, you and I, have tackled through the International Bladder Cancer Group for many years. We also have been part of the AUA EAU guidelines, NCCN, et cetera, and there's often a confusion or a disconnect between what constitutes intermediate risk bladder cancer because some guidelines now, especially, allow certain high grade patients to be considered intermediate risk. So could you share with us a little bit, first putting on your hat as someone who was part of the EAU guidelines for many years and then putting your hat as a practical urologic oncology expert, what constitutes intermediate risk non-muscle invasive bladder cancer, in your opinion?
- [Fred] So Ashish, that's actually a good and very difficult question. You have to realise, I think the biggest group of non-muscle invasive bladder cancer patients are those with, let's say, the definition of intermediate risk, and if I'm called by a colleague about, you know, what should I do and this is that patient, it's never low risk, that simple, it's also almost never high risk, it's actually always intermediate risk because that's a big group with a lot of more or less different definitions. So what I exclude as intermediate risk is patients with T1 tumours, CIS and with high risk or high grade tumours, I think high grade tumours, to be honest, are almost always high risk. In the American guideline, you have PT1, low grade. My pathologist claims it doesn't exist, so whenever it does exist, it's very rare. So I think to be practical, D1 tumours are high risk. And then of course, solitary, small, low grade, primary, non-recurrent, that's of course low risk and everything in between and that makes it quite difficult is intermediate risk and that's why the things we did with the International Data Cancer Group, adding to that definition of you know, usually it used to be in the EAU classification, intermediate risk was everything else, everything that was in between.
So it's not very useful, but it is a big group, and what we did with the International Bladder Cancer Group, I think makes sense to differentiate between the lower risk intermediate risk group and the higher risk intermediate risk group because I think treatment, intervascular treatment and follow up will differ substantially between those two ends of the intermediate risk group. - [Interviewer] Yeah, so share with us a little bit because you know, clearly we don't want to under-treat patients, at the same time we don't want to over-treat them because obviously they're older, frail, we don't want to keep doing that. So share with us a little bit as to how you go through the multiplicity, the recurrence history, all of the things that the IBCG has in the risk classification, and how are you factoring this in when you're counselling patients between the different treatments? And we talked a little bit about this in a different episode, BCG, chemotherapy, active surveillance. How are you using those different parameters?
- [Fred] Well, Ashish, with regard to overtreatment and undertreatment, I think if we misdiagnose, it's almost always under-diagnosis because we miss things. Meaning that we usually under treat and we rarely over treat, I guess. Because, you know, if there is 20 tumours, it's not five, it's maybe 40, but it's at least 20. So meaning that I think overtreatment wouldn't happen a lot, it's usually undertreatment and in the intermediate risk group, that's also beyond the risk of progression is not that high. So there is some room for interpretation or playing around a little bit. What I think are factors that are really useful is, the number of tumours, again, we know now from the blue light studies that we do miss a lot of tumours. So it's not a black and white figure. If you see five tumours, it might be more. With regard to the recurrence rate, I think that's quite hard because we know that the patient, we know the patient, he already had a tumour per definition because otherwise it's not an intermediate risk. So that's something I really do use the tumour five years ago or the tumour five months ago, that's a big difference. And size, we already talked about it again in another episode. Whether it's 2.7 or 3.1 because the average or where you make the difference is three centimetres. That's very difficult to estimate. So also size for me is not a very big issue because I guess if you have a five centimetres tumour, it's almost always T1 or high grade.
I haven't seen a five centimetres low grade tumour in my whole life maybe. So I think the recurrence rate, that's important number, okay, size, okay, but predominantly recurrence rate then of course the final pathology grade and stage. - [Interviewer] Yeah, I think the size thing that you mentioned about five centimetres, I think it might be a system thing because I think in the Netherlands a lot of patients are more cognizant, they go to their doctor. Here, I will see eight, nine, 10 centimetre tumours just because the patient can't afford to go to the physician or doesn't go. So that's something that might be a regional as well. Talking about those practical issues, anxiety, cause, et cetera, talk a little bit about your standard surveillance and follow up tools that you use, cystoscopy, blue light, white light, urinary markers, et cetera, for these patients with intermediate risk cancer. - [Fred] So obviously, if you look at the guideline, you should do cystoscopy every three months in the beginning, four months, six months, then sometime yearly. And a cystoscopy is of course not something you would really like to have. I've had one just to feel how it feels and you know, it's not bad, but to be honest, I'm happy that I had one and I hope I don't have to have one again.
So you have your cysto then cytology is of course very subjective. The specificity of cytology is certainly good, but the sensitivity, certainly low grade tumours, is not very good. The question is whether you would be very unhappy if you miss a low grade tumour, but okay. Imaging I guess is in intermediate risk tumor's not really an issue. Maybe if you had a tumour in the prostatic urethra, you want to know whether there are metastases or you had the tumour near the orifice of the urethra, you want to know whether this is something like an open urinary tract tumour or nodes. But in real intermediate risk, those chances are relatively limited. And then you have, and I know that is currently a big discussion everywhere, you have your markers, your urinary markers, there are good epigenetic urinary markers currently available, both sides of the ocean in Europe and also in the US, and most of them that have been commercially available are going to have a very high negative predictive value, meaning that if they say there's nothing in the bladder, the chance that there is in the bladder something is one or two percent, it's very good. Maybe even better than our eye. And you know that I started with one of those markers during the COVID period, we were not allowed to see patients very often. So we said, well you know, I can't do a cysto with your iPhone, I have to do something. So we send them a marker, it's done at home, they send the result to the lab, we get the results from the lab again for the patient, and since then we've been alternating a cystoscopy with a urinary marker. And so far it goes very well.
The doctor's happy, the patients are happy. If you look at all the costs involved, it's actually even cost effective because patients don't have to come, they don't have to travel, you don't have to do a cysto, you don't need a nurse, et cetera, et cetera. So what we currently do, and I think that really is gonna be the future, and there have been now some first studies proving that or let's say proving, showing that it's safe to at least for a part, alternate cystoscopy with a marker. I know it's not in the US guideline, it's more or less coming in the European guideline, and I'm sure that within a few years we will also use markers in follow-up with patients, certainly, and intermediate risk patients where again, you know, even if you miss one, it's not a major disaster. - [Interviewer] So Fred, share with us a little bit because you know, again, what you have done for many years and what I do too, is after a patient has been free of disease for a year or two years, the interval of follow-up is extended, right? It's not every three months, it's not every six months, it's sometimes once a year. So how practical is it to skip the yearly cystoscopies and use a urinary marker? Do you do that often where you find patients don't want to even come in every year for a cystoscopy?
- [Fred] Well, it's not so that patient don't want to come in. Most patients have a good relation with them so more or less like seeing me and I like seeing them. So that's not the issue. They see the bladder because it's a cystoscopy with a television. So they see that that's something that they like to see. But again, I think using the marker is certainly not worse than doing cysto. You have to realise that you do also pick the upper urinary tract of the mark because after something in the upper urinary tract, you won't see it with cysto and you do see it with urinary marker. So yeah, some patients realise that they don't want to travel and some are not refusing cystoscopy or asking whether they can be checked only with a marker. And I think, although again, you know, that's not standard of care, it's not the guideline yet. I think it's safe, and so far I haven't had, fortunately, any big problems or large tumours that I missed that I would otherwise have picked up with a cysto. Be aware of that. So I think that's something we can do safely in the very, very near future. - [Interviewer] And how often do you get imaging, Fred, for these patients with intermediate lower risk cancer? - [Fred] Well, of course, you start with imaging if it's a primary tumour.
We do usually CTU, we have a one day diagnosis thing. So they get a cysto and cytology or a marker and CTU the first day they come there, and the next day they get the result. So you have already a good imaging of the upper urinary tract, meaning that if it's a real intermediate risk patients and then of course there's no prostatic urethra involvement, there's no lymphovascular invasion or histological subtype because that's high risk, so you're quite confident that the risk of something nasty progression nodes is very, very small, and I would probably only do a urinary tract imaging on indication, for example, if the marker's abnormal and you don't see anything in the better, things like that, but not standard anymore. And I've been trained with an IVU, if you still know what that is, every year. - [Interviewer] Yeah, for those that don't know what an IVU is, it's an intravenous urogram and in many situations it actually has a higher resolution than CT scan, but as Fred, you just alluded, not many people still know how to get it or read it. So I think it's a lost art, right? - [Fred] It is, it is. - [Interviewer] Exactly. Do you use MRI? - [Fred] Yeah, we use MRI. Again, that's really something that you can use if you're talking about non-muscle invasive bladder cancer in the higher risk group, the different shade between T1 and T2 because that's a major difference in treatment. T1 is basically intravesical treatment, T2 is basically radical surgery, and MRI does very well on that. We are now talking about intermediate risk where that discussion probably is not really relevant. So I guess MRI in this specific group of patients wouldn't have additional value.
- [Interviewer] Right. And that's the point I wanted to highlight because a lot of people I see are getting MRIs even for low risk and intermediate risk patients. I don't think it's necessary. It's a cost that we can save. Fred-- - [Fred] Yeah, you can better reserve your MRI time because in my hospital a lot of MRI time goes to the prostate and if you have some neurological MRI time also spares some for good bladder indications. - [Interviewer] Absolutely. Well Fred, tell me a little bit about how you treat these patients with intermediate risk bladder cancer. Do you use the risk stratification to decide between chemo and BCG? You have BCG in the Netherlands, so do you use BCG in more patients? How do you consult patients on what you're gonna use to treat them with? - [Fred] Well, of course, by the time that you're deciding on treatment, you have got your pathology, you know your patient, you know whether he's old or fit, whatever, you know whether it's multiple, you know the grade, et cetera, so you have the full picture. And again, with the IBCG classification, I don't think it happens very often that I only have given one installation. Usually you'd like to give something more. I basically go for intravesical chemotherapy in the patient with intermediate tumours unless there are really several factors like a higher recurrence rate because I think that's very important and the multiple tumours. So I would guess in a minority but still a minority of those patients I will start with BCG and if I would do that, I would go for one year, not really for the three year maintenance, what you would do in very high risk patients with CIS because that's of course high risk and also chemotherapy, I would give for one year, and the schedule that I use, I've been trained with that, is four times weekly and then 11 times monthly.
Why? I don't know. Everybody has a sort of different schedule but more than a year for intravesical chemotherapy is not fair use. So that's what I basically do. And of course, you discuss it with the patient that they are really... Especially the ones with a higher recurrence rate, they really want to prevent more recurrences, then I would go from BCG because that's better, with regard to the recurrences. Otherwise I guess, inverse chemotherapy to start with is certainly not a bad option. - [Interviewer] Yeah. You know, it's interesting you mentioned that here in the US what I do and what's in our guidelines, it's once a week for six weeks and then once a month for a year or 18 months depending on which agent you're using. Have you started advising more patients on active surveillance? - [Fred] Yeah, but not the intermediate risk group. I guess that's really something that you would do in the low risk population, and if you then see a small tumour again after, and you know your patient, and you know it has been a Ta, low grade, obviously not if it has been a high grade T1 but if it's been a low grade Ta and you see one again after nine months or 12 months, they see that, they see it on television, on screen, I see it, they talk a bit about that, and then the choice, of course, to take them again to the OR, 75-year-old guy, he has to have anaesthesia, he has to stay in the hospital for a day, or you say, you know, the chance that that will grow, of course, is present, but let's wait for six months, see again, and I think I do that more and more. And there are some studies now from the Italian group, for example, that have shown that the chance that you miss progression is really very, very limited. And of course, there's nothing 100% and zero percent, but I think it's a safe way of doing that. And yes, I do that. And if I lecture on that, I ask patients or a urologist, do you do active surveillance in the prostate cancer? Yeah, you do. Do you do active surveillance in small kidney tumours? Yeah, you do. Do your active surveillance in small bladder tumours?
Nobody does that. I don't understand, but I do. - [Interviewer] Yeah, no and active surveillance is something that we, through the IBCG have also used our risk ratification for the intermediate risk cancer. So when you said the low risk, if you have zero points on the IBCG scale, those patients in, when we looked at the Italian group and we retrofitted them, you could go three years without needing a TURBT. If you had one to two points you could go about a year. So even with one to two points you could go about a year with active surveillance without requiring a TURBT. So I think that's something that we really need to counsel our colleagues and our patients a little bit more about. Recently there have been trials that have been reported out and agent was approved recently by the FDA for ablative therapy to replace TURBT, right? The mitomycin gel formulation. What are your thoughts on ablative therapy? Because I know in Europe there have been studies done with just straight chemotherapy as ablation. What are your thoughts on ablative therapy in the place of TURBT? And I guess it's in between active surveillance and TURBT, right? So ablation as an intermediate step. - [Fred] Well, I know the older studies, we had EORTC study a very, very, very long time ago with mitomycin C, and then the final ablation rate was around 50%. And in those days the ablated area was still biopsied. So you still have an operation and the other 50% still had TUR. So you know, I have not become in favour of ablative therapy because of those experiences. I know now that for example with the gel, maybe the response rate is higher, but still you will have to give, let's say quite a lot of drugs intravesically to get the same result as you get with a small TUR because it's not a big operation, but then you do have the final pathology. So I guess there will be indications for ablative therapy if the patients can't be anaesthetised or have a very big prostate, you can't reach the tumour, things like that. But otherwise, I probably would go... I'm a urologist, I do surgery, so I would probably go for TUR and not really ablative therapy unless there is a contraindication for TUR, let's say.
- [Interviewer] So, yes, also, Fred, we talk about ablative therapies and I think it's really important, as you mentioned, that in patients where it's contraindicated to have a TURBT, if they've recently had, for example, a stent placed or active anti-regulation, it might be something to consider. But yes, for the most part, patients can have active surveillance, office fulguration, TURBT, I think that's very important. - [Fred] Ashish, if you are considering a patient for ablative therapy, that's also of course not a very big T1 grade three. So it's probably also a smaller tumour for which you might as well do, which is even safer, active surveillance or office filtration. So I still think the indication for ablative therapies is not that big but anyway, we'll see. - [Interviewer] Are you using predictive tools nowadays, Fred? I mean, there's so much work being done with using predictive tools. There's cystoscopy, AI, there's AI using biomarkers, et cetera. Are you using predictive tools in this intermediate risk group of patients to identify which patients might do better with active surveillance, with chemo, with BCG, et cetera? Any insights there? - [Fred] No. I guess you have, and that's of course more experience. You have your pathology, you have the recurrence rate, you have your patients, you have the treatment that you've given, that will give you an idea about your final outcome. I've written my thesis in 1991. There was a calculator in there for prediction of whatever. I've never used it.
And you have the same... The URTC had one, I think the AUA had one. I think they're quite complicated, and for sure, you should, if you're gonna use a calculator, you should check it in your own practise whether it's also applicable in your patients, in your country with your treatment. So it's not something I use a lot, but I know that my residents, if they're not experienced enough, of course they do use the, for example, the ERC risk calculator to decide how often to do cystoscopy, what kind of treatment to give, and I think that's okay. If you have not enough experience, then I think it's good to be helped by, in this case, a calculator. Whether AI is going to help, I don't know. I think in the two ends of the disease, the very low risk patients, AI will give you a good answer. And then the very high risk patients, AI will give you a good answer. Especially in the intermediate risk group, I think that's quite complicated and I think a good multidisciplinary discussion with your colleagues and the patient might be better than using AI, but the future will learn. - [Interviewer] Yeah, no great points, Fred. I want to thank you for highlighting the personalization, it's very important, the balance between vigilance and treatment and of course doing the appropriate right treatment for the right patient at the right time. - [Fred] Sure. - [Interviewer] Thank you so much. It's always a pleasure chatting with you. - [Fred] Okay, thank you, you're welcome.
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