Roberto Contieri: Okay, thank you very much, Dr. Kamat, and thanks to UroToday. It's always a pleasure to join this conversation. And yes, I'm going to talk about optimal maintenance schedule for mitomycin C. And we all know that mitomycin C is an antineoplastic antibiotic, but also an alkylating agent. And once activated in the cells, mitomycin induces DNA cross-linking and cell death. So it's used in non-muscle-invasive bladder cancer spectrum is wide and different. We can use mitomycin for early single instillation after TURBT. We can use mitomycin as adjuvant intravesical therapy, but also as neoadjuvant intravesical therapy. There are a few studies evaluating the efficacy of mitomycin before TURBT, but also it can be used for chemoablation and it can be also delivered with alternative strategies such as hyperthermia. We could say that despite its age, mitomycin C is still rocking because of its efficacy and cost-effectiveness in this patient population. And that's why EAU Guidelines, but also the IBCG Guidelines suggest to use intravesical chemotherapy including mitomycin C as adjuvant treatment after TURBT in intermediate-risk tumors in place of BCG.
It makes absolutely clinical sense because in particular in low-grade intermediate-risk patients, we want to use BCG in a later stage of the disease, maybe in high-grade disease. So we want to save that card for a later stage. That's why mitomycin C still plays a very useful role in this patient setting. However, there is still an unmet clinical need, as you said, Dr. Kamat, that still we don't know which is the optimal schedule we should give the mitomycin. That's why we performed this study aimed to assess the impact of maintenance therapy on recurrence-free survival in patients with Ta NMIBC. But also we want to identify the optimal number of instillations during maintenance. This was a retrospective multicenter study, enrolling patients with intermediate-risk Ta NMIBC undergoing TURBT plus adjuvant intravesical mitomycin C in 13 Italian centers between 2010 and 2023. The primary objective was to assess the impact of maintenance versus no maintenance on recurrence-free survival. While the secondary objective was to identify the optimal number of instillations during maintenance associated with a reduced recurrence risk. So we included patients who received at least induction, defined as weekly mitomycin C, with or without maintenance, defined as administration of monthly instillation of mitomycin C. Of course, in this case, maintenance was different among the different centers which adopted center-specific protocols.
Endpoints were recurrence-free survival and high-grade recurrence-free survival. We performed Kaplan-Meier and multivariable Cox adjusted for clinical risk factor, but also we used a landmark analysis, because we wanted to exclude those patients who received a low number of instillations during maintenance due to early recurrence. So that's why we excluded these patients censored before 12 months. Then we used classification and regression tree analysis in order to identify the optimal number of instillations during maintenance, which were associated with reduced recurrence risk. So the cohort included 292 patients who received at least one induction cycle. 249 patients received the maintenance therapy with a median number of instillations of six instillations. You can see in Table 1 the baseline demographic and tumor characteristics of the patients. And after a median follow-up of 33 months, 147 patients recurred, including 56 patients with a high-grade recurrence and 14 patients with a progression to muscle-invasive bladder cancer. Of course, progression to muscle-invasive bladder cancer in this patient population is slow as expected.
When performing the landmark analysis, of course, we excluded 96 patients for recurrence-free survival and 65 patients for high-grade recurrence-free survival, according to what we have already said, early recurrence or censoring before 12 months. Here you can see the Kaplan-Meier for recurrence-free survival stratified according to maintenance, any kind of maintenance, which means monthly instillation versus induction with no maintenance. And as you can see, the two-year recurrence-free survival was 55% in no-maintenance group compared to 78% in the maintenance group. So at the Cox regression, we found that maintenance with mitomycin C significantly reduced the recurrence risk with a hazard ratio of 0.13. Then we found that maintenance was associated with a low risk of recurrence, but we want to know how much is enough for maintenance instillation. That's why we performed this classification and regression tree analysis, which found the optimal cutoff of monthly instillations at more than six. So then we stratified the cohort according to this new cutoff as you can see in the table, and we reran the analysis for recurrence-free survival, but also for high-grade recurrence-free survival.
As you can see, recurrence-free survival in the short-term maintenance, which means six or fewer monthly instillations, was 67% compared to 86% in patients who received more than six monthly instillations. So at Cox analysis, there was a statistically significant difference between long-term and no-maintenance patients, but also between long-term patients versus short-term maintenance patients. These results were not confirmed for high-grade recurrence. We found no statistical difference for high-grade recurrence-free survival stratifying patients according to the maintenance. Of course, there are several limitations in this study. For example, the retrospective design, but also the heterogeneity of maintenance regimens across centers. The follow-up duration was reasonable, but probably it was not sufficient to capture late recurrence. And this, together with the fact that in our database, the subsequent treatment after recurrence were not captured, might have influenced the oncological analysis for high-grade recurrence. However, in conclusion, according to our results, we can say that maintenance with mitomycin C improves recurrence-free survival. We found a cutoff of more than six instillations, which represents the optimal threshold for reducing the recurrence risk. A potential effect on high-grade recurrence cannot be excluded, but we failed to demonstrate it.
However, until new intravesical strategies become standard, we know that there are lots of ongoing trials studying new strategies, but also new drugs in this patient setting, intermediate-risk patients. Nowadays, mitomycin C still remains a key component of clinical practice. Thank you very much.
Ashish Kamat: Thanks, Roberto. Again, the data that you presented solidifies what we know about chemotherapy for patients with bladder cancer. The fact that induction alone is not enough. Malmström did this many years ago where he showed that you need the maintenance with mitomycin, and the only way mitomycin is going to beat BCG is if you have mitomycin maintenance. And of course, if you have BCG maintenance, then BCG beats mitomycin maintenance too. But this is good as it's a reminder that even in the modern era, the longer you do the maintenance therapy, the better it is for the patient. Clearly it's a risk-benefit ratio. How much do you do? How much is too much? So even though you didn't present that in your manuscript, and I know sometimes it's hard to do that with these database analyses, do you have a sense as to which is the ideal patient where you need to go beyond induction alone and which is the patient with, in some ways, the worst prognosis in the subgroup analyses where you should go beyond two years? Any thoughts there?
Roberto Contieri: Okay, thank you for this question. Of course, it's not easy. And well, ours was a retrospective analysis including lots of centers, but we have data on this. For example, I think that the stratification of intermediate risk, I mean low-grade intermediate-risk patients made by the IBCG works very well. So we can use those risk factors, I mean, dimension, time from last recurrence and so on, to choose the right patients. Of course, it's not always easy to use this substratification in clinical practice, but I think that in this case, the data can add to the stratification and this data can help us to choose these patients. And also this classification system for intermediate risk by IBCG has been validated in different settings. For example, active surveillance, but also patients receiving mitomycin C. So that's why I think that this is a really useful tool to adapt our strategies in our patients.
Ashish Kamat: So I guess what you're saying, Roberto, is that once your group does the analyses based on those scores, we should have you back on UroToday to do another session. Is that correct?
Roberto Contieri: Yeah, that's correct. I think that we can work on this. Of course, we have to expand our cohort. Because if we want to substratify the cohort, 200 patients is a small number. So I prefer to work on this and collect more data, and then perform this analysis.
Ashish Kamat: And again, I was half-kidding, but half-serious as well because I think it's really important for us to be able to counsel patients appropriately. And we in many ways know that mitomycin, gemcitabine, they have similar efficacy with some overlap. Pulling data together and coming up with a risk stratification to help guide the duration of maintenance across all chemotherapies I think would be very useful. Roberto, thank you so much for taking the time. Always a pleasure to have you and stay well.
Roberto Contieri: Yeah, the pleasure is all mine. Thank you very much.