Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas. And it's a great pleasure to welcome to the forum once again, Dr. Roger Li. Roger, thank you for taking the time. Today, we're really excited to have you on, because you're going to be talking about something that we have worked on together at the IBCG. Something that's really very important as a group effort really came out of a retreat. But you are the lead, so of course you are given the privilege of presenting to all of us the recommendations from the IBCG for intermediate-risk non-muscle-invasive bladder cancer. So take it away.

Roger Li: Thanks so much, Ashish, again for the invitation. And also it was a great pleasure to work with you and others on this project. As you know, intermediate-risk non-muscle-invasive bladder cancer has become front and center in the clinical trial space for urologists. And despite that, there's a lot that needs to be formulated in terms of just its definition, risk stratification, management strategies, and clinical trial design. And that's essentially the goal that we had over the last summer with the International Bladder Cancer Group meeting. So as part of the meeting, we came out with the guidelines, and so I'll just kind of take us through some of the highlights from this white paper that we put out. So first of all, the definition for intermediate-risk non-muscle-invasive bladder cancer is not agreed upon by all guidelines, but us at the International Bladder Cancer Group, we think that if the patients were to have high-grade tumors, that they automatically should be classified as high-risk patients.

And that intermediate risk really should be including those patients only with low-grade tumors that have risk features, such as having recurrent tumors, multifocal tumors, larger tumors, with diameters that are greater than or equal to three centimeters, or low-grade T1 disease. And if the three-tier grading system is used in some countries, that TA grade two tumors should also be automatically considered as intermediate risk, regardless of whether or not it's a new diagnosis or a recurrent tumor. We also agreed, according to the WHO recommendations, that in the case of mixed tumors, if there's less than 5% high-grade disease, that this should be the cutoff for consideration to be classified as intermediate risk in NMIBC. And more importantly, also, this is very important for clinical trial inclusion purposes, that if a patient were to have a distant history that is greater than three years of a solitary high-grade TA tumor and then recurs with low-grade disease, that that patient is not excluded from such trials, as is currently the case in many trials.

Of course, we know that TURBT is the backbone of disease management for intermediate-risk bladder cancer, but there are also some nuances that need to be stressed. So rather than stressing about the need for really precisely staging the disease, we know that by and large low-grade tumors are going to be very superficial, and so there's not a need for re-staging TURBTs by and large for staging purposes, nor is there any need for us to sample the muscle layer for these diseases in order to prevent any risk of bladder perforation. And then in terms of treatment, of course we know that we came up with the IBCG risk stratification in the past, and really we leveraged this risk stratification to formulate which patients are viable candidates for active surveillance for ablative therapy as well as for adjuvant intravesical therapy. For those patients who are considered at low risk with zero to one IBCG risk factors, these patients are prime candidates for active surveillance, because we know that we want to lower the treatment burden for these patients. And of course, we also have to demonstrate that these patients have a negative urine cytology, because there's no biopsies that are required during the active surveillance process. The Italian group has put forth some criteria in terms of the candidates for ablative therapy, and that includes patients with exclusively low-grade TA disease less than or equal to five papillary lesions on cystoscopy that are less than one centimeter in diameter, and also a negative urine cytology to prevent any patient with an occult high-grade disease being enrolled. Office-based energy ablation with or without tissue sampling is going to be considered for these patients with small recurrent tumors that appear to be low-grade.

Then finally, the implementation of adjuvant intravesical therapy really should be commensurate with the number of risk factors, and that is the IBCG risk factors that the patients have. For those patients with less IBCG risk factors, that they may be more befitting of intravesical chemotherapy. And for those with three IBCG risk factors, they're considered to be really high risk, and this has been validated with many different validation cohorts now that they are at high risk for even progression to high-grade or even muscle-invasive disease such that intravesical BCG is warranted in those patients. And then finally, in terms of surveillance, so we agreed that there wasn't any sufficient evidence to support the routine use of enhanced cystoscopy in the clinic for these low-grade patients. And also, the use of cytology in such patients with low-grade disease is not routinely recommended unless if you're considering the patient for active surveillance or ablative therapy to rule out high-grade disease. Cytology obviously can be considered for those patients at highest risk for grade progression. That is those patients with greater than or equal to three IBCG risk factors. And then finally, to reduce the exposure to x-rays, upper tract imaging in the form of CT urography or MR urography is not routinely recommended in the surveillance of these intermediate-risk NMIBC patients. And finally, we touched upon the clinical trial recommendations for both adjuvant trials as well as ablative trials.

For the adjuvant trial, therapy should really be used in the comparator arm or the control arm, and the type of therapy that's selected to be used in the control arm should really reflect the number of IBCG risk criteria for those patients. The primary endpoint for these studies should be recurrence-free survival, and the aim is to achieve a clinically relevant effect size of 10% increase in two-year recurrence-free survival rate. Ablative therapy on the other hand, should be sort of a proof of concept that the agent is efficacious in the setting, and that it should really be limited to patients, again, with exclusive low-grade disease in the past. That of course there should be thorough documentation for the number of tumors, multifocality of tumors, and the diameter of the tumors at minimum, at baseline. And finally, the endpoint for those trials should be complete response rates seen at three months following induction therapy and also recurrence-free survival in those patients that are afforded a complete response. And finally, in terms of biomarkers, so as we know, there are no current urinary biomarkers that have been demonstrated to have the same efficacy in terms of surveillance to replace cystoscopy in this setting. And there are a lot of ongoing efforts and we look forward to future study readouts in this setting.

Ashish Kamat: Thanks, Roger. Thanks for taking eight months that we worked on this the whole day and a half retreat, and then summarizing in such a nice succinct manner for our audience. It really distilled everything that we've done. And of course, all the recommendations and the text is in the paper that you referenced, and we'll put a link to it at the bottom. Just for those that are listening in, that may not have access to the original paper, could you just go through what the IBCG scoring factors are, so people know the zero, the one to two, the three or more?

Roger Li: Yeah. So the IBCG risk criteria was really originally put forth by yourself back in 2014, a group that was led by yourself back in 2014, and then was refined in a more recent paper that was led by Wei Shantan that put forth these risk factors with the diameter of the tumor being greater than three centimeters, multifocality, recurrent tumors, and also previous history of intravesical treatment being the risk factors that will predict for a higher rate of recurrence in these patients with low-grade disease. And of course, we know that the more of these risk factors that are seen at baseline for many of these patients, the more likely it is that they will develop recurrence. And also, if they have greater than or equal to three of these risk factors, as was proven by the original paper, but also by validation cohorts now that was done out of Europe, that there's also a risk for progression to high-grade disease and sometimes even muscle-invasive disease.

Ashish Kamat: Yeah. And just because sometimes I'll get the question from people about the frequent recurrences, which is one score, more than one per year, and then early recurrence, within a year. And people are like, "What, aren't they the same thing?" They aren't really, because if you think about it, say somebody has a tumor today that's low-grade recurrent, but the last one was more than one year ago, that doesn't fall in the less than one year category. But assume that the previous two tumors were six months apart, right? So today's tumor is still considered an intermediate risk, even though the last one was not within one year. But if the last one had been between nine months, then yes, that falls in. So there are five criteria that we propose, and of course, zero, one to two, and more than three.

And honestly, when we proposed it back in 2014, it was really based on expert opinion, which is a lot of these things, including BCG unresponsive definition, all of this comes about, right? So it's really good to see that independent cohorts of data using, of course, even the AI platform and using other artificial intelligence coming from Toronto and others, have sort of validated those risk factors. Which also then brings me to a question to you, Roger, which is kind of related to this, but also related to a lot of the work that you do. The clinical parameters that we see so far when it comes to intermediate-risk bladder cancer, high-risk advanced disease seems to trump a lot of the molecular markers. Can you shed some light on what was discussed about molecular markers in our discussion on intermediate-risk disease and why we didn't think that we needed to include those as of now as ready for clinical use?

Roger Li: So that's a great point. I think when looking at the entire scope of the work that's been done on molecular biomarkers, first of all, I don't think that there's any urinary biomarkers that have been proven to be just as effective a cystoscopy of visualizing the tumor and detecting the presence of tumor. But also, in terms of risk stratification. I think there's a lot to be said about just the nuanced histologic description of these tumors, that even if you were to present the same tumor to 10 pathologists, that they may not give you the same answer in terms of what grading the tumor may be, and hence the high-grade versus low-grade, and also the grades one to three. So there's a lot of nuances in the grading of the disease already. And I think, despite a lot of the efforts that have been done so far in terms of PathAI, as you alluded to, and others, molecular sequencing efforts, low-grade tumors, for some reason, there hasn't really been as much effort in this realm compared to high-grade disease. And I think, especially from the risk stratification perspective, if you really think about the biggest risk factor that we're considering is the risk for recurrence.

And to me, I think when you're considering the risk of recurrence, it's really the entire bladder that's at risk. And so you may not necessarily find out what is driving the recurrent tumors from looking at the tumors themselves. There may be kind of a bladder-centric biomarker that we have to concentrate on. Whereas if you look at the risk of progression, it may be that you can find clues within the tumor themselves to predict whether a patient may have high-grade tumors in the future. But with all that being said, I think there's so much that's going on. I'm especially intrigued by the PathAI and what we're able to do as looking at high-grade tumors already being able to predict whether patients are going to be able to respond to BCG. But in addition to that, also looking at the low-grade tumors, whether or not patients may develop progression to high-grade disease. From just looking at the pathology slides, these are widely available. And I think with such an AI platform, we can really leverage these to help stratify patients onto different treatment strategies.

Ashish Kamat: Yeah. No, I agree. And I just want to emphasize to the folks listening that we did say that for patients with zero risk factors, we could consider even active surveillance, right? Because those patients have close to a zero, as close to zero risk of progression as you can get. But in those that have three or more risk factors, and you could just do this based on clinical parameters, so far at least, the biomarkers and the PathAI hasn't matched the clinical parameters, but in our series and the series from Europe, the progression to muscle-invasive disease was as high as 8%, and these are low-grade tumors, right? So I think we have to be really cautious and emphasize to everybody listening that intermediate-risk bladder cancer is the most common cancer that we urologists see. It's a very heterogeneous group. And that's why we put forward that effort that, again, you summarize so well. So Roger, always a pleasure having you on here and thanks so much for taking the time.

Roger Li: Thank you so much for having me.