Managing High-Risk NMIBC
Transcript: Smart risk tools to personalize NMIBC care
Félix Guerrero-Ramos, MD, PhD, FEBU, 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 the podcast titled Expert voices: Navigating non-muscle invasive bladder cancer. I'm Ashish Kamat, neurologic oncologist in Houston, and it's a pleasure to welcome to today's episode, which is "Stratification and prediction in non-muscle invasive bladder cancer: personalizing care for patients with smarter risk assessment". Doctor Felix Guerrero Ramos, who is an expert, really needs no introduction, joining us from Spain. And it's a pleasure to have you Felix.
- [Felix] Hello everybody, hello Ashish. Thank you very much for the invitation. The pleasure is mine to be here.
- [Ashish] So Felix, you know, one of the things that patients and doctors often face is how do we approach risk stratification for non-muscle invasive bladder cancer. So tell us how you do it in your clinical practice?
- [Felix] Well first of all, we should highlight that stated by the EU guidelines, for example, risk stratification is a must in non-muscle invasive bladder cancer patients because it will guide our treatment decisions and also it will guide our follow up schedule. In our clinic we usually tend to use the EAU 2019 guidelines, the previous version, but sometimes we also use the new version of these guidelines, the EAU21 and later years, which you know, have also a website and an app for telephones. And what we do is we assess with the different clinical and pathological features, the risk of these patients in order to put them in different boxes to try to tailor the therapy the most accurately to these patients.
- [Ashish] So you know, it's great that you actually publicly stated that you tend to use the 2019 recommendations because honestly, that is something that I use as well. It's much more clear, it's easy for patients to understand and it is similar to the IBCG risk stratification. Right, and for those in the audience that might not be quite familiar with it, could you tell us exactly what that risk classification is, the 2019 EAU classification?
- [Felix] Yeah, this is a very simple one. One of the main characteristics of this classification, it's that it's an expert consensus. It's not based on individual patient data like EORTC, CUETO or EAU 2021. But it's very simple 'cause we have that any high grade, any T1 any CIS are high risk patients or even those Ta low grade, which are multiple recurring and bigger than three centimeters. Those low grade patients would be those patients with a primary Ta low grade, small tumor, less than three centimeters, which is a single tumor and there's no CIS and all the rest of the patients will be intermediate risk tumors. For me, this is one of the main drawbacks of the classification, that the intermediary risk is kind of a mess of an exclusion criteria where any patient which does not fall either in the higher risk or in the low risk category, will fall into the intermediary risk. But as you know, we have some of the tools like the IBCG sub classification of intermediary according to different risk factors.
- [Ashish] Yeah, and just for the listening audience, there's a separate episode that we did on the intermediate risk patients where we went into a lot of detail with the IBCG risk classification. So I encourage those to listen to that podcast. So Felix, when you are sitting and talking to a patient, you know, sometimes patients come and they don't really want to hear the details of the risk classification, but they still want to know why you're recommending a certain treatment to them based on their risk of recurrence and progression. So can you guide us and tell the audience how you go about that with your patients? How do you discuss this with them?
- [Felix] Well, when a patient has non-muscle invasive bladder cancer, the first thing we say is that they don't have currently at the moment a life-threatening disease, but we have to look at the risk of progression. And I explain to my patient that risk of progression means that the tumor can go into the muscle layer and that implies that 50% of the patients then will die from their disease no matter what we do. With that in mind, I explain to my patients that according to the risk of having that more advanced disease and more dangerous disease, we look at certain clinical and pathological features. And that's why depending on that risk, we decide either one treatment or a different therapy.
- [Ashish] Great, and I think patients really appreciate to hear that, right. So now when we're looking at the different risk categories, the low, intermediate and high risk, or what treatments do you offer, for example, for patients with low risk disease, intermediate and high risk? Just briefly, between the low and the high risk patients.
- [Felix] It's very easy and it's according to the clinical guidelines, all the guidelines recommend for low risk patients, we usually do not recommend any adjuvant therapy, just follow up, for low and intermediate risk patients, we try to use, if it's feasible and there's no complications, a positive instillation of chemotherapy in the first 24 hours after the TURBT. For high risk patients, we are recommending BCG one to three years. We don't recommend BCG three years to every patient. We can speak on that later. For intermediate risk patients, we tend to use the IBCG sub classification to decide whether to go to either observation or BCG or even chemotherapy, standard chemotherapy, hyperthermic chemotherapy or any other options.
- [Ashish] Yeah, no, that's wonderful. That's very clear. And now let's get into something that's a little bit more muddy, right? So when you're recommending immunotherapy with BCG for patients that are high risk, clearly that is something that is standard of care and has the longest track record. But within that high risk category, you have patients that have very high risk features, you know, some that have multifocal CIS, some that have T1 grade disease. How do you decide which patients you are going to offer BCG to? How do you essentially track these models and then make your decision and who you're gonna recommend cystectomy, who you're gonna recommend BCG, et cetera?
- [Felix] Well, in general, for those patients with very high risk disease, of course we explain the very high risk of progression to muscle invasive bladder cancer, which is a life-threatening disease as I said before. And for these patients, we usually tell them that radical cystectomy is the oncological, the safest oncological therapy. And that's true, but as we know, and there is evidence on that, it can be an overtreatment in certain patients. So in spite of advising them about radical cystectomy, there are some of these patients where we offer that BCG could be a reasonable first line therapy and see how it works. Not all the very high risk patients are the same. Of course, if we have patients with neuroendocrine or different histological subtypes, we might go or we might tell the patient more about radical cystectomy. But for example, if you have a patient with a T1 high grade three centimeters plus CIS who's 72 and is a very high risk patient, we can recommend BCG. Always be a reminder, radical cystectomy is the most radical therapy and the most safe therapy. But we can tell these patients that we can do a try with BCG before going to radical cystectomy because it does work. There is some evidence on that, on the performance of BCG in the very high risk group.
- [Ashish] Yeah, and if you look at the risk classification system, especially you look at the prognostic tools that the EORTC puts out, it's important again to recognize that that 40% risk of progression is in patients not treated with BCG. Right, and in today's day and age, at our center for example, the progression rates are in the single digits for the most part. And I'm sure in your center too, when BCG's done appropriately for the appropriately selected patients, they can do quite well. But Felix, you know, you've done this a long time, I've done this a long time. We always will sometimes meet patients that have extremely high risk disease in which something is telling you that this patient should really be considered almost like their muscle invasive. Could you share with our audience what are some of the danger signs or the red flags that make you tell the patient, listen, if you were me, I would take my bladder out.
- [Felix] Yeah, one of the main red flags is lymphovascular invasion for sure. We know that Lymphovascular invasion predicts a much poor prognosis than those patients who do not present lymphovascular invasion in their tumors, and this is important to ask your pathologist to look for that and to report that, even if it's negative, so that you can state that there is not lymphovascular invasion. If there's a patient with a T1 high grade tumor with CIAs or even with without CSAs, T1 high grade with lymphovascular innovation for these patient that will certainly recommend radical cystectomy as an upfront therapy. And then as I said before, patients with histological subtypes or patients with multiple T1 tumors with CIS or tumors in the prosthetic urethra, even if we rule out there's a T4 tumor after looking at the prosthetics trauma. For these patients with very high risk features, I would recommend a radical cystectomy because they're uglier tumors to me.
- [Ashish] Yeah, these are great points. Do you use molecular classification or any of the emerging models and et cetera, AI models in your decision making?
- [Felix] No, we don't. Outside clinical trials, we do not do that. We've been looking at some molecular markers and we are using some micro RNA based things with a BlaDimiR test, which is a test we patented and we are developing. But all this see within the clinical trial or the research setting, there's no molecular profiling that we do in the current clinical practice.
- [Ashish] Yeah, and I think that's another important point because there's a lot of these AI-based tools, there's a lot of these modeling that are very promising and we're all excited to see where this takes us. But currently they should be used a little bit with caution, more of a supplement or compliment to how you counsel patients rather than an absolute, which is critical because we get patients sometimes that come to us with, you know, literature printed from the internet and they think that they could put in the numbers into ChatGPT or something like that and it'll spit out the recommendation. So that's a little bit of a dangerous thing that we need to educate our patients about. But clearly there are molecular insights that will influence our treatment decisions, right, down the road. So for example, if you have somebody that has BCG unresponsive disease, and we'll talk a little bit about BCG unresponsive, are you then sending these tumors to be profiled or are you only doing this for clinical trials?
- [Felix] Nope, we're doing this only for clinical trials. Currently the only clinical trials for which we have targeted therapies are those with intravesical Erdafitinib. So these patients who are BCG unresponsive, the only patients with BCG unresponsive disease are those papillary tumors who are BCG unresponsive that are candidates for a clinical trial with Erdafitinib and they undergo GFR screening mutations or fusions, which is the target of this therapy.
- [Ashish] Now speaking of BCG unresponsive, so that's a definition that is very confusing sometimes, not only to, you know, the average physician, but also experts and patients, et cetera. Right, that's a definition that was proposed to the FDA by expert groups here in the US that I was, you know, fortunate to be part of and along the others of course. And the FDA adopted it and it led to an explosion of single arm studies. Felix, let me ask you to enlighten our audience and explain what exactly is BCG unresponsive definition and how do you use that in your clinical practice?
- [Felix] Well, BCG unresponsive includes those early relapsing and refractory tumors. This means any patient with a high grade recurrence up to, let's see, there are two groups, those patients with CIS and those patients with Papillary only disease. For patients with CIS, any high grade recurrence up to one year after completing completing BCG would be BCG and responsiveness status. And for those patients with Papillary only disease who experience a high grade recurrence up to six months after ending the BCG therapy would be considered BCG unresponsive. And here I would like to congratulate you because you also sometimes said in certain scenarios and certain meetings, and it's true, these definition was developed for the development of new drugs and clinical trials. But some months ago there was a clinical validation of the definition where we see that the definition that you and the other group, the group of experts developed is useful in clinical practice and it also differentiates the prognosis between the different patients who are not responding to BCG. So there was this external validation, this was a very nice paper and it showed that it can be also applicable to clinical practice.
- [Ashish] Yeah, and I think that was critical, right, because like people were automatically using this in clinical practice without actually studying it. And that's a little bit of a cautionary tale that we want to put that we want to have more drugs approved, we wanna have single arm studies, but we don't want patients to unnecessarily suffer a label if it's not gonna help them get the best treatment. So again, let's stick in this sort of arena, right, patients that are high risk and now you are considering between BCG and chemotherapy or other treatment options for the naive patient, how do you make that decision?
- [Felix] Well those patients who are high risk for sure, well first of all it is not only the risk specification, the risk stratification, it's also the patient profile. If I have a 92-year-old lady who is ECOG three and has a high risk tumor, I would probably not administer BCG and plus I would probably not follow her up with cystoscopies, just ultrasound or even if you have any hematuria come back. I mean you have also to tailor the treatment to the patient, not just to the tumor and that's important. But in general, for high risk patients, we use one year of BCG, we usually keep three years of BCG for CIS, for those very high risk patients who are not undergoing upfront radical cystectomy. For intermediate risk patients, we're trying to tailor the therapy according to their BCG risk factors. It's true that most patients have at least one risk factor. So not many of these patients will undergo observation. And we usually decide between intravesical, normothermic chemo, some of the patients will undergo hyperthermic chemotherapy and small proportion of the patients will undergo BCG if they present several risk factors or especially if their tumors have failed to produce intravesical chemotherapy.
- [Ashish] And again, is the BCG for one year mainly because of the shortages or is that something that you've transitioned to even if you had plenty of BCG?
- [Felix] Well, in my center, I started coordinating the oncology unit in 2018, 2019, six, seven years ago. And they had always been doing one year. So it was new for them when I started with three years for these very high risk patients. But looking at our data and also at the burden we have in our clinic and at also the rate of completion oof the treatment of the patients, I believe that for most patients with disease, one year is enough. Although we know that three years according to the meta-analysis performed previously is better, but most of our patients, I think one year is enough. So that's why we keep three years, we have a lot of patients in our clinic, there's a lot of burden and we have to keep three years for those highest risk patients. But as I said, even without a BCG shortage, we tend to use one year BCG with our patients.
- [Ashish] Yeah, that's interesting. That's a little bit different from what is on our recommendations in North America and the guidelines because for high risk patients, if they're high grade, it's recommended that you consider three years of maintenance therapy and you can decrease it to one year if there's a reason such as Ta disease or there's BCG shortage, I think you're saying the same thing because you use three years for CIS and you use three years for T1 disease, so automatically you're using one year for Ta patients, right?
- [Felix] Yeah, that's something like that, yeah.
- [Ashish] Okay, great, great, great. Now Felix, if a patient becomes BCG unresponsive, what's your counseling? - [Felix] Well, when a patient becomes BCG unresponsive, first of all have to advise the patient of the risk of the disease at that moment. And we know that BCG, which is currently like the best intravesical therapy, will not provide much benefit. And the main recommendation is radical cystectomy, but radical cystectomies also another treatment for some patients. The problem is that we don't know who will benefit from radical cystectomy or from other novel therapies or alternative therapies. So recommendation is to undergo radical cystectomy. However, we offer our patients being enrolled in clinical trials. We are high volume center and we have a lot of clinical trials. And sometimes if the patient is fit for radical cystectomy or refusing radical cystectomy and also unfit or refusing clinical trial, we can use any of the different bladder approaches. In our case, we have available and hyperthermic intravesical chemotherapy. So we offer them.
- [Ashish] Yeah, and I like what you said because you know, it's very important to incorporate patient's desires and you know, the quality of life measures because at the AUA meeting recently it was presented and it was a little surprising to some to see that some patients actually have a better quality of life when they have their bladder taken out rather than when they leave the bladder in and undergo multiple rounds of treatments. And some of us, you know, believe that it's partly due to anxiety, right? The risk of having the bladder in place and trying multiple things, not knowing if it's gonna work might make the patient more anxious. You know, Felix, it's always a pleasure to chat with you and we're coming up on the closing minute or so. So let me ask you at a broad perspective, what is your take home message to the listening audience on an NMIBC risk stratification? Where do you see that risk stratification going in the future and what would the ideal model look like for you?
- [Felix] Well, first of all, for the audience, a risk stratification is a must in non-muscle invasive bladder cancer because it is the best way we have nowadays to tailor the therapies to our patients, either intravesical or systemic therapies. Number two, the future models will probably integrate big artificial intelligence data and also some molecular profiling. But I think this it's not close as we need validation for these molecular classifications and they are also expensive and not easy to implement in certain smaller or community centers. But for the audience, if you want to tailor the treatment to your NMIBC patients in the best way, you must stratify these patients in the different risk categories.
- [Ashish] That's great Felix. Again, I want to thank the audience for joining us on Expert Voices. I wanna thank Doctor Guerrero Ramos for his expertise and stay tuned for the next episode.
- [Felix] Thank you very much Ashish and thanks to the audience for their attention.
Developed by EPG Health. This content has been developed independently of the sponsor, Pfizer, which has had no editorial input into the content. EPG Health received funding from the sponsor to help provide healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content. This content is intended for healthcare professionals only.
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