Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston, Texas. And it's a pleasure to welcome Niyati Lobo, who is currently Chief Resident in the UK at the Royal Surrey NHS Foundation Trust. Niyati spent some time with us here at MD Anderson as part of her external rotation through her Fulbright scholarship and did a lot of good work, one of which was looking at our BCG-treated patients at MD Anderson Cancer Center.

Ashish Kamat: And one of the projects that she was involved with and which was published and gained a lot of press recently was looking at the updated EAU prognostic risk groups and seeing whether or not patients treated with BCG are appropriately reflected in that. And Niyati, it's a pleasure to have you here to discuss your work, and take it away.

Niyati Lobo: Well, it's a real pleasure to be here. So thank you so much to yourself and also to UroToday for giving me the opportunity to share this work, which we recently published, as you said, in European Urology Oncology. So non-muscle-invasive bladder cancer represents a heterogeneous group of patients with varying risks of recurrence and progression. And we know that after TURBT alone, up to 45% of cases will progress to muscle-invasive disease within five years of diagnosis. So accurate risk stratification is really crucial in establishing treatment recommendations, surveillance schedules, and also for selecting patients for inclusion into clinical trials.

Niyati Lobo: Now until recently, the European Association of Urology Guidelines for NMIBC recommended stratification of patients into three risk groups, these being low, intermediate, and high risk. And these risk groups were derived from the EORTC genitourinary tract cancer group risk tables and for recurrence and progression. However, this risk stratification was updated last year by Sylvester et al. on behalf of the EAU to include a separate, very high-risk group. Now, this very high-risk group was created to identify patients with a higher probability of progression to muscle-invasive disease compared to the previous EAU high-risk classification.

Niyati Lobo: And as you can see here, these new risk groups provide a risk or probability of progression at one, five, and 10 years. And they've been endorsed by the most up-to-date EAU guidelines. However, when doing this analysis, Sylvester et al. excluded patients treated with BCG. So whether or not this risk stratification can accurately stratify BCG-treated patients is unknown. And as such, our aim in doing this work was to evaluate the applicability of these updated groups in a contemporary cohort of NMIBC patients treated with BCG.

Niyati Lobo: So to do this, we performed a retrospective review of BCG-treated patients at MD Anderson over an 80-year period. And patients were analyzed according to the receipt of at least induction and adequate BCG. Now, that's as defined by the US Food and Drug Administration, the IBCG, and also the EAU. And for the benefit of those listening, that is at least five out of six induction installations plus an additional two installations given within a six-month period.

Niyati Lobo: What we then did is we used an online calculator made and created by the EAU, which is available at nmibc.net to assign an updated risk group to each of our patients. We then used Kaplan-Meier methods to estimate time to progression and also probability of progression at one in five years, and then compared those progression probabilities with the updated risk groups in our series to those reported by Sylvester et al. And finally, we assessed discrimination using the C-index.

Niyati Lobo: So firstly, a little bit about our cohort. This table provides a summary of both patient and tumor characteristics, and you will see that in total, 529 patients received at least induction BCG. And of that group, over 90% went on to then receive adequate BCG. The majority of our cohort were male, and you can see that when we applied the 2019 risk stratification to our cohort, approximately 76% of patients were classified as high risk. But when we then went on to apply the 2021 updated risk factor groups, we found that 52% roughly were classified as high risk. And then, about 22% as very high risk.

Niyati Lobo: I'm going to show you our sort of that set of results. So what you see here are figures showing time to progression curves according to the updated risk stratification. So on the left is the at least induction BCG group and on right, using the adequate BCG group. And what we see here is that these updated risk groups are able to successfully stratify progression risks in our MD Anderson cohort. However, what we then find is that the groups actually overestimate progression risks in BCG-treated patients.

Niyati Lobo: So compared to the EAU-predicted rates, which you'll see on your right outlined in blue, in patients receiving at least induction BCG and adequate BCG, we found lower progression rates at one year in the very high-risk group, and then at five years in the high and very high-risk groups. And you can see here that the greatest difference in probability is actually seen at five years. So you see 16.7% in the at least induction group and 14.9% in the adequate group, and that compares to 40% in the EAU-predicted group.

Niyati Lobo: We then did a separate analysis where we included patients with primary CIS. And you might ask why we did that. Well, I think the reason for that was because when Sylvester et al. did their analysis, they actually excluded primary CIS patients. So we wanted to see what difference this would have, if any. And actually, we found very, very similar results.

Niyati Lobo: Our last finding was that treatment with BCG reduces the discriminative ability of the updated groups. And as you can see here, we've got a C-index of 0.63 and 0.64 in the MD Anderson series, and that compares to a C-index of 0.8 in the EAU-predicted series.

Niyati Lobo: So moving on to the discussion of our results, in updating the existing EAU prognostic factor risk groups, Sylvester et al created a very high-risk group with a progression probability of approximately 40% at five years. And you can see that in the table on the left, where it's highlighted. And the recommendation for patients that fall into this very high-risk group is that immediate radical cystectomy be seriously considered.

Niyati Lobo: However, when comparing progression probabilities in our very high-risk group with those reported by Sylvester et al., we found lower probabilities in both the at least induction and adequate BCG groups. So, therefore, even though the very high-risk patients have been identified as potentially benefiting or requiring immediate cystectomy, our data suggests that this may not necessarily be the case. And as such, there may actually be a role for BCG in the treatment of very high-risk patients where patients are, but that needs to be confirmed by other studies before drawing firm conclusions.

Niyati Lobo: So our results are not unexpected. In fact, they're consistent with the superiority of BCG over chemotherapy and preventing progression. And we know that BCG is able to prevent or at least delay progression, and it's actually for this reason that Sylvester et al. excluded BCG-treated patients from their analysis. And again, when the CUETO group validated the EORTC risk tables in a large cohort of BCG-treated individuals just over a decade ago, they found very similar findings.

Niyati Lobo: I want to acknowledge the limitations of this work. Obviously, this is retrospective single-center series. Additionally, selection bias may have excluded patients that particularly [inaudible 00:10:08], so I'm talking about patients with high-risk NMIBC that were managed with immediate cystectomy, for example.

Niyati Lobo: Another limitation that I just wanted to mention pertains to the group that received at least induction, but not adequate BCG. So almost 50% of this group had either high-grade T1 or T2 progression at the first post-BCG three-month cystoscopy. And as a result, underwent cystectomy instead of maintenance BCG. However, you might argue that means that the adequate BCG group is biased towards patients who did not recur or progress early, but actually, this cohort of patients represents only about 6% of our entire cohort.

Niyati Lobo: So in conclusion, we found that the updated EAU risk groups are able to successfully stratify progression risks in our MD Anderson cohort. However, they overestimate the risk of progression in patients treated with BCG, and that's particularly seen in the very high-risk patients. Our feelings are that these findings should be used in conjunction with the updated risk to guide clinical decision-making and to counsel patients with higher risk NMIBC about their risk of progression with and without BCG treatment. So that's it. Thank you.

Ashish Kamat: Great. Thank you so much for that presentation. So, of course, we've talked about this periodically and had multiple discussions. But for the purposes of our audience, if you could highlight how you think people should use the EAU risk calculators currently given the caveat, that would be useful.

Niyati Lobo: So the possibility is extremely useful, I think, for counseling. And as I pointed out earlier, there's a website where you can easily put all the information into a calculator, and it gives you the risk or the probability of progression pretty straight away. And I think that's useful in counseling patients about their risk of progression. But I think that as we've seen, the caveat of this is that you need to sort of temper that with, "Well, okay, how does that risk change if you treat patients with BCG?" And that risk is obviously lower.

Niyati Lobo: So I think it's really important to be able to tell patients, "Well, yes, this is your risk of progression, but actually that risk of progression will change if you are treated with adequate BCG. So, I think it's extremely useful for counseling patients, especially those high-risk patients. We know that it can be difficult to make those decisions because you're talking about radical surgery, which carries the risk of morbidity and mortality versus BCG, which is obviously far less invasive.

Ashish Kamat: And then using, maybe not the data that you presented, but other data from our center and other centers, [inaudible 00:13:35] shown that in current contemporary series of patients treated with appropriate selection and BCG, the progression numbers on the single digits, as compared to historic controls where people often said that about one-third of patients progress and one-third will die of their high-grade non-muscle-invasive bladder cancer. Are you seeing that in your center? I know with the caveat that you're still a trainee, but are you seeing better outcomes of patients treated with BCG in your experience compared to what you're reading in the older literature as well?

Niyati Lobo: Yes, definitely. And I think those earlier numbers you've quoted, that was something I learned for my exams, but I think we are definitely seeing better outcomes with the use of TURBT with enhanced cystoscopic technique of blue light. Obviously, at the moment, we have been affected by the BCG shortage, so patients aren't getting the maintenance in the way they would've before. But certainly, you're absolutely right. Contemporary outcomes are definitely improved compared to what we've seen historically.

Ashish Kamat: Great. Again, from a trainee perspective, what are some of the pearls that you would want to impart to, say, someone sitting for their boards, not just again specifically based on your paper, but about your experience with patients with non-muscle-invasive bladder cancer selection criteria, how can we best select the patients for appropriate therapy?

Niyati Lobo: I think the first thing is adequate risk stratification. I definitely point people towards the EAU risk calculator. I think it's a great tool, and I think it's just being familiar with some of the literature that's been published on BCG and, of course, discussing all of our patients in sort of a multidisciplinary team setting. I think all of those things are really important, and I think that certainly from my training, I think when I came to your lab, I learned so much about BCG that I didn't know before.

Niyati Lobo: And I would encourage trainees that are involved in treating bladder cancer patients to really get familiar with the literature around BCG because certainly, for myself, there are a lot of things I really didn't know, specifically about maintenance treatment, the length of maintenance treatment, how we make sure we have good outcomes, the importance of duration over dose, all of these things are things that I learned sort of from being in your lab. And so, I'm grateful for that and, yeah, we'll definitely pass that on to my peers.

Ashish Kamat: Oh, you're most welcome. It was a great experience both ways. Lastly, in closing, if you could just briefly summarize the findings from the study that you performed and where do you think you could take it going into the future, like next steps?

Niyati Lobo: I would say that the summary of the findings of that, the 2021 updated EAU prognostic factor risk groups overestimate the risk of progression in BCG-treated patients. And as such, when it comes to counseling patients with high-risk bladder, non-muscle-invasive bladder cancer, those risks of progression with and without BCG should be considered against the morbidity of radical cystectomy. And I think that going forward, future work needs to focus on definitely validating these risk groups in other BCG-treated cohorts. Obviously, our work just looked at the MD Anderson series, and I think it would also be really interesting to be able to develop a separate scoring model to improve the prediction of outcomes specifically in BCG-treated patients.

Ashish Kamat: Excellent points. And again, just to wrap it around and bring it home, I want to emphasize that the risk stratification proposed by the EAU has evolved over the years. The most recent update in the year 2021 and, again this year 2022, does include certain characteristics that may not be easily factored in unless you use the nomogram, but it still is based on data. But it's important to recognize that those nomograms or risk calculators are for patients who are not treated with immunotherapy with BCG. So it's a good counseling tool to use for patients if there's no BCG available or to allow patients to make a decision on, say, early cystectomy if they choose not to get BCG. But once they're able to get appropriate therapy with BCG, those risk calculators are not really as appropriate or as relevant to that population.

Ashish Kamat: So again, thank you for taking the time, spending it to us today, and best of luck in everything you're doing.

Niyati Lobo: Thank you so much for having me.