Roberto Contieri: Thank you, Dr. Kamat. It's always a pleasure to join this conversation in UroToday.
Ashish Kamat: So today we're going to be talking about something that's very important to discuss. When we look at high-risk non-muscle-invasive bladder cancer, T1 high-grade bladder cancers clearly are one of the highest risk tumors. And for those patients, we've always in the guidelines recommended doing a second resection, mainly because of the fear of understaging poor quality TURBTs and missing T2 disease. Now, in this study here, very provocative in some ways, you studied whether the second TUR can be omitted. So looking forward to hearing what the results show.
Roberto Contieri: Okay. Thank you very much. So I'm particularly related to this study for two reasons. One, because it started from a discussion during my first year of residency after a journal club with Dr. Hurle and Professor Giorgio Guazzoni. And it was actually the first abstract I presented at EAU conference back in 2021. So that's why I'm really happy to show the results of this study that was published last month in European Urology Oncology. So we know that EAU guidelines suggest to perform a second resection after an incomplete TURBT in case of the absence of detrusor muscle and in all T1 tumors. And this makes sense because the rationale is to detect residual disease, as you said, improve staging accuracy and reduce recurrence and progression. If we look at older series, we see that the rate of residual disease at second resection is very high. It's more than 60%.
And the rate of muscle-invasive bladder cancer at second resection is 15%. And this is also true in patients with the detrusor muscle in the first resection. So that's why perform a second resection is suggested by EAU guidelines. But when we put all this consideration on the side, removing residual disease, improving outcome, improving staging, we have also to consider that a second resection has an impact on the quality of life of the patients, has an impact on the use of resource from the healthcare system perspective, and also can impact on the time to get adjuvant therapy such as BCG. So the idea of this study was that a more selective and response-guided approach could reduce morbidity and resource use without compromising oncological safety. So the aim was to evaluate the oncological safety of a selective approach in which we avoid ReTUR in selected patients.
HuNIRe trial was a prospective observation multicenter trial, including patients with T1 bladder cancer in five Italian hospitals. Inclusion criteria were patients with a complete initial TURBT stated by the surgeon and with the presence of detrusor muscle in the pathological specimen. Patients who underwent prior BCG with concomitant or previous UTUC, histological subtypes or lymphovascular invasion were excluded from the trial. So as you can see, the study design was quite simple. Patients with complete resection and detrusor muscle in the specimen with a T1 tumor avoid the immediate second resection and undergo urine cytology at three, four weeks. And then if negative at flexible cystoscopy, at first its six week. If both are negative, patients avoid the second resection and undergo BCG, and standard BCG and follow-up. Otherwise, the patient is candidate to second resection.
We included 90 patients, and you can see the baseline characteristic of the patients in the table. And of these 90 patients, only 26 underwent second resection, 11 because of positive urine cytology, and 15 because of positive cystoscopy. Among those patients who underwent second resection per protocol, in 27 of them, there was no tumor at second resection with only 15 patients having persistent T1 high-grade tumor, and no one was upstaged to muscle-invasive bladder cancer. With a median follow-up of 26 months, only 24 patients experienced a recurrence, including 5 who progressed to muscle-invasive bladder cancer. The two-year recurrence-free survival was 69%, while the two-year progression-free survival was 91%. When we evaluated among the HuNIRe cohort, the patients who underwent second resection versus patients who avoid the second resection, there was no difference in recurrence-free survival and progression-free survival. Lastly, we performed also a comparison among the HuNIRe cohort, the protocol cohort with a retrospective cohort of patients who underwent the same centers to standard second resection and BCG.
You can see the characteristic of this retrospective cohort in the table compared with the HuNIRe cohort. As you can see, the second resection pathology in retrospective cohort was negative in 56% of the patients with T1 high-grade tumors in 14% of the patients. Of course, these results are biased because of the retrospective nature of the comparison, but still, as you can see, the two-year recurrence-free survival and progression-free survival were quite similar among the two cohorts with no difference at Cox regression analysis. And this is also evident at Kaplan-Meier, as you can see on the right of the slide. So in conclusion, we showed that avoid second resection in selected T1 patients is feasible, and we use this response-guided strategy. So our idea is not to avoid second resection at all, but just to identify a high-risk population who perform a second resection. With our approach, we spared 71% of the second resection, and our short-term oncological outcome showed that there were no differences in oncological outcome. So with this approach, we could reduce unnecessary surgery, morbidity, and healthcare cost, and also to avoid delay in BCG initiation.
Of course, we need longer follow-up and easily a randomized clinical trial to confirm these results, but I want you to reflect on one point. A few years ago, I think three years ago, the group of Professor Gontero published this feasibility study of a randomized clinical trial of second resection plus BCG versus upfront BCG. And what they found is that it is feasible, of course, but to perform such a study, we need to screen a huge number of patients. So that's why I think that despite its limitation, HuNIRe, it's likely to remain the most robust evidence supporting a selective and carefully reasoned de-intensification strategy for the near future. And I think that the strength of our studies, that it introduced an idea that we can carefully select the patients who need a more intensive approach. Thank you very much.
Ashish Kamat: Thank you, Roberto. That was a very nice presentation and a very provocative study. First off, congratulations to you and your team on doing this. A couple questions I want to ask you. In the patients that you compared in this particular cohort with the retrospective cohort, the incidence of no tumor or finding a secondary tumor was different. So why do you think that in the more modern era, when I presume you're doing better resections, you had higher percentage of patients with residual disease?
Roberto Contieri: So this is a central point of the study. So we have to think that patients who has no detrusor muscle and with a complete resection were not included in the study. To rule the complete resection, the surgeon had to complete a surgical checklist as EAU guidelines suggest. So I think that one of the variable that impacted in the study is that the surgeon who knows that the patients will be enrolled in a study will think twice before say, "Okay, my resection was complete." So this is a point. Also, the retrospective cohort, probably we don't have the data, but in the HuNIRe cohort, there was 30% of the patients undergoing en-bloc resection. And we know that this technique has implemented a lot in the last few years. And we know that with en-bloc resection, the resection is more accurate and we remove also what we think is healthy tissue around the tumor. So I think that this might have impact on the rate of presence of tumor in the specimen. And also, I think that the quality of TURBT is the most important point in our study. I think that we stress it a lot, the importance of the quality of TURBT. And for example, at the Humanitas University, we have a training program for TURBT, which we think it's a niche procedure, but it's the most important procedure for a patient with a non-muscle-invasive bladder cancer. So I think that all this thing helped us to present this favorable data.
Ashish Kamat: Right. No, I totally agree with you. TURBT is an extremely important part of every bladder cancer patient's journey, whether they're non-invasive or muscle-invasive disease, and it's really crucial that we do this right. Let me ask you a follow-up question about the cytology and the cystoscopy, because you had a false-positive rate for tumor on repeat resection, the patients that did not have a residual disease. Was that more on the patients who you took to the operating room because of a positive cytology or was it a positive cystoscopy? What was more likely to contribute to the false-positives?
Roberto Contieri: So I think that the contribute to false-positive was 100% for patients with negative cytology and positive cystoscopy. And we expected this. I think that cytology are a very important tool that we should use in our daily practice. Of course, the cystoscopy is operator-dependent. And again, in this case, we set a trial in which we avoid a second resection. So of course, the surgeon or the urologist who performed the cystoscopy knows that if he defined that the cystoscopy negative, the patients avoid the second resection. So I think that also the fear to miss some tumors led to overestimate the presence of the false-positive results. And I can see, because also the cystoscopy is run out three, four weeks after resection. So of course, we have some red lesion in the bladder due to probably the previous resection. So I think that's why we still have a negative rate of pathology, but still, we avoid second resection in 70% of the patients. So it's okay to have some false-positive.
Ashish Kamat: Yeah. And again, I want to congratulate you and just make a slight editorial comment because I think one of the things that we have to keep in mind was that the study was done at a center that has expert resectionists, expert bladder cancer physicians. And I think before we can translate this into the general population, we have to make sure that we have certain words of caution because the risk of understaging is a real risk. If this is done in a high volume center with expert cytopathologists, so your cytology was a very crucial part of the whole journey. And if the resection was done by expert bladder cancer surgeons who do this all the time, I mean, not to say that others aren't good surgeons, but if bladder cancer is only 1 or 2% or 10% of somebody's practice, then it's not something that they might do all the time. So I think this allows us to rethink this paradigm maybe in high volume centers of excellence, but also for those patients who might be very sick. They might be very sick, they might be older, more anesthesia complications, and you've done one ReTUR and you're trying to see, can I avoid a ReTUR? In those patients I could see maybe using this paradigm. So Roberto, again, congratulations on the study. Congratulations on completing it, and thank you for taking the time.
Roberto Contieri: Thank you very much, Dr. Kamat.