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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at the MD Anderson Cancer Center. And it's my distinct pleasure to welcome to the forum today Professor David D'Andrea, who's joining us from Vienna. Dr. D'Andrea specializes in outcomes research. He's a urologic oncologist at the Medical College of Vienna. David, thank you so much for taking the time today and sharing with us your study and your perspectives on en-bloc versus conventional resection of bladder tumors. So David, take it away.

David D'Andrea: Thank you, Ashish, and thank you for your kind invitation to this amazing platform that you created. So today, I will share with you a couple of insights of our eBLOC trial. We'll go a bit more in the detail, as you said, with further perspectives. So basically, we have been doing TURB for over a century. And the technique has not improved over the years very much. As we can see here is a resectoscope from the sixties. What this basically did is a forceps that took the tumor in chunks and were removed during flushing. This is what most of the urologists are doing today during a TURB, just piecemeal resection and flush it all out. But as you know, and you agree with me, TURB is the first and probably the most essential step in the management of patients with non-muscle invasive, or the first diagnosis of bladder cancer. So there is an unmet need for improvement in this field.

What are the goals of TURB? These are a couple of my thoughts that I would like to share with you. Probably everybody agrees in common sense, but I just would like to frame it in these two slides. So the complete eradication of the tumor is the first step in oncologic surgery. The good quality of the specimen is essential to allow the pathologist a good report. We want to achieve negative surgical margins in our resection and we want to reduce the morbidity of the surgery to, in the end, improve the oncological outcomes of the patients.

So why do we need a good TURB? Still again here, five points. We know in non-muscle invasive bladder cancer, we have high recurrence and progression rates. So accurate resection should be the goal to reduce these recurrence rates. We have limitations in imaging. So the staging of the TURB is essential in this step to then allow good risk stratification of the patients in planning adjuvant therapies. The outcome is not only dependent on cancer biology, but also, as we said, on the quality of TURB.

Regarding this review, it was recently published, also you co-authored on Nature Reviews. Five points were identified as recurrence mechanisms from a clinical perspective. At least three of these mechanisms can be influenced by a good TURB. So in this picture, you can clearly see the advantages on the left-hand side the en-bloc resection delivers compared to a piecemeal resection, where you have a lot of charring and difficulties orienting the tumor. When the pathologist then receives such a specimen, he is, of course, happy and the diagnosis is almost immediate, also with the stage.

So back in 2018 when we designed our eBLOC study, there were only a couple of single-center randomized trials investigating en-bloc versus conventional TURB with different primary outcomes, mainly focused on the recurrence rates. They all turned out to be negative. So when we planned this trial, we wanted to put a focus on the quality of the resection, and this was our primary outcome. We measured the quality of the resection by the presence of the detrusor muscle, as was reported from several groups, especially also from this Scottish group.

So the trial was designed as a one-to-one randomization open label, and we needed almost roughly 400 patients with a primary tumor. Inclusion criteria were less than three centimeters, or equal to three centimeters, and we allowed a maximum of three tumors in each patient. We randomized 384 patients between 2019 and 2022. 219 tumors were resected with the en-bloc technique and 233 were resected with the conventional TURB.

So for the primary outcome, what we found is that resection with an en-bloc TURB achieves an 80.7% rate of the detrusor muscle in the specimen compared to 71.1% in the conventional. This difference of almost 10% was significant. And so we met our primary endpoint.

Regarding secondary outcomes, I would just like to share with you three of these. The perforation rates, which are quite important for the positive management of the patients. What we saw was that with the en-bloc TURB, we had almost half of the perforations compared to conventional TURB. The obturator reflex was also half of the conventional TURB, which probably reflected also in fewer perforations. Residual disease was indeed quite high in both cohorts. At this point, I would just like to mention one aspect of this point, that we had a very small amount of patients who got a second look TURB. So we can see 26 in the en-bloc TURB group and 34 in the conventional TURB.

This probably was mainly because this was basically a COVID and post-COVID trial. So we had a lot of restrictions in TURB, and most of the patients could not undergo a second look TURB for logistical reasons. So we are facing here a highly selected population in which probably the operator was not sure if the resection was complete, and forced a little bit the re-TURB. If the resection was considered complete, probably the patients underwent more advanced therapies in this context.

So regarding subgroup analysis, this is shown also in our paper, but I would like to focus on two aspects of this. Overall, we see that in a subgroup there is a trend that favors en-bloc resection, but particular significance is given to smaller tumors below two centimeters and the clinical stage TA. And this is probably where the comfort zone of the surgeon is. And you get probably deeper and try to avoid too much damage to the bladder. Another interesting aspect was that patients who were resected under PDD from blue light had a much higher rate of the detrusor muscle, if resected in the en-bloc compared to the conventional. So another aspect was the margin rates in our trials. The deep resection margin and lateral resection margin was available in 117 and 133 tumors in total. The deep resection margin was 0% positive in older patients. Compared to the lateral margin, which was positive in 6%. Only one patient turned to have T1 on re-TURB.

This slide shows a little bit the clinical judgment of the surgeons during surgery. So as we can see, the clinical stage TA indeed translated into a high rate of TA at the pathological staging. But in T1, things get a little bit more tricky. And almost only 50% of the patients with a clinical T1, in the end, turned out to be also pathological T1. With regards to the detrusor muscle, we see here that if the surgeon declared that the detrusor muscle was present in the specimen, there was a fairly high amount of the detrusor muscle also in the pathological report. But if the detrusor muscle was absent, still we had 50% of patients having a detrusor muscle at the final pathological report. The final slide on our trial recurrence-free survival, which was also a secondary outcome. In line with literature, as we can see here, we could not see any difference in recurrence rates in this cohort.

So how does our trial compare with the general literature? Basically, there is one trial with a similar design that was published earlier this year in the same journal. They had a similar design to our trial: single-center, randomized trial, fewer than three tumors, smaller than three centimeters. What they found compared to our trial was a much higher rate of the detrusor muscle in the en-bloc cohort, but also in the conventional cohort. This trial turned out to be negative. And similar to us, they did not find any difference in recurrence rates. So comparing these two trials, the first thing that one wants to discuss is probably the surgical experience, how they differed. Indeed, we had, if you see on this table, we had a lower rate of residents performing the en-bloc resection. In the trial from Barcelona, there were many more.

Could this have influenced the outcomes? Probably. Let's see, in our trial, if we go back to the subgroup analysis, we see here that the junior consultants, so those with less than five years' experience, had indeed a higher rate of the detrusor muscle, but this was not significant in the resident or the senior consultant cohort. Perforation rates differed definitely in both trials and this could also be an explanation for the difference between the two groups. We had fewer perforation rates and this could also probably translate into the detrusor muscle rates compared to the other trial. Regarding general literature, what we see here, this is a meta-analysis published one year ago from a fellow from our center. In all the trials published previously, we have an overall almost 90% rate of the detrusor muscle in the specimen compared to a 68% of detrusor muscle with the conventional TURB, which is more or less aligned with our trial.

And finally, I want to conclude with the same meta-analysis showing the recurrence rates, which again are similar in the two cohorts, as I said in this meta-analysis. So in conclusion, what are the further perspectives for en bloc resection? In my opinion, every surgeon should perform en bloc resection whenever it is feasible; it'll definitely allow you a better staging and this makes your pathologist happier. Can we avoid a second resection? This is a big question that still remains open and definitely needs further evaluation in the future. And we will not have to forget that other mechanisms may influence recurrence and this should also be taken into account in managing the patient. So I thank you very much for your attention and look forward to the discussion.

Ashish Kamat: Thank you so much, David, for that succinct presentation and congratulations on completing an important surgical trial such as this. I think one of the things that your results and your discussion highlights is that it's very important to do a good TURBT, right? That's the critical first step in the management of our patients. And how you do that TURBT is personalized to the actual situation. So if the particular tumor or the patient is amenable or suitable for en bloc, that should be how you do it. If that patient is not suitable for en bloc, in other words, if the tumors are large, etc., then you don't do en bloc. I think that's the key message that we need to drive home to everybody listening, do the best TURBT that is possible. And use whatever tools you need or whatever technique you need to make it the best TURBT. What do you think?

David D'Andrea: Absolutely. I totally agree with you. As we said, the TURB, particularly in the first occurrence of a bladder tumor, is the most essential step because you have to correctly stage the patient in this case. Because every time you do a TUR, you alter the biology of the tumor. And you have a huge impact and influence the outcomes of the patient, in terms of recurrence and probably also the progression rate. So as I mentioned, the goals of the TUR are to eradicate the tumor completely and to do it in a proper manner because it's common sense that cutting through a tumor is against every oncologic principle. So in no other tumor entity in urology do you just cut through the tumor, make it in pieces, and then suck it out. An en bloc resection should be performed if feasible, of course, every time you can. As you said, with any tools you have. With laser, with a loop, flat loop, whatever you need to do it. But if it's feasible and probably the size as you mentioned is the only limitation in this case, you should go for it.

Ashish Kamat: Yeah, it's interesting you made that comment because I used to say the same thing 20 years ago, we shouldn't be cutting through tumors and it's oncologically unsafe. But then even with an en bloc, what happens is you cut the tumor, but it floats around in the bladder. Then there is the risk of seeding. So I think it's very important to emphasize that point that just because you've done an en bloc resection doesn't mean that it should exclude that patient from consideration of perioperative chemotherapy, single-dose instillation if it's appropriate. If you have a perforation or if you think the patient's definitely going to need BCG, you may avoid perioperative chemotherapy based on the data. But I think that's an important point that I want to emphasize. Just because you've done en bloc, does not mean you don't need to follow the other oncological principles.

With that in mind, I do want to ask you one question because people make a big deal of the whole perforation issue, etc. I think one of the key things that we need to emphasize to people is that when appropriate, again, not for low-grade tumors, but if you can visually assess the tumor and you think it's going to be T1 or high grade, you almost want to go deep enough that you have a micro-perforation. So can you comment a little bit on how you guys define perforation and whether your findings, because some people say, "That's too high a rate." Do your findings have an impact on how you would now approach deeper resections for potentially aggressive T1 tumors, for example?

David D'Andrea: Yeah, absolutely. Thank you for highlighting this. The one thing also within the trial, what we found is that when you perform an en-bloc resection, you go slowly through the layers. So even if you see a perforation, which is defined by seeing the perivesical fat, so over the detrusor muscle, you move millimeter by millimeter. And you are very accurate in this type of resection. So even if you have a small perforation, you can adjust and move up to the layer. So the perforations that you have actually in the en-bloc resection do not affect then the perioperative, postoperative chemotherapy. Because it's not that deep perforation that you usually have with having one loop that is one centimeter or two centimeters in depth. These are controlled perforations that in our trial absolutely did not affect the administration of postoperative chemo.

Another aspect that you mentioned, which is also very important, is that the en-bloc resection, as I said, is only a piece of the puzzle. So doing a good en-bloc does not solve everything. You have to fit it. So the en-bloc resection is one piece, but also the perioperative chemotherapy is another part. And as the tumor is floating around the bladder where you can also be seeding, as you mentioned, another field that in the future should be definitely explored more is also neoadjuvant chemotherapy. And also these new agents that are coming and also new devices that are coming on the market for the administration of drugs in the bladder.

Ashish Kamat: The whole concept of ablative therapy, neoadjuvant ablation, all of that. We could have a whole hour on just the nuances of TURBT, but in the interest of time, I want to ask you one last question before we close. And that is, how do you recommend people approach extraction of these tumors? Obviously, if they're small, it's easy. But say someone stumbles in and does an en-bloc resection and the tumor is just that little bit larger than you can pull out through the sheath. Briefly, what are your tricks that you use to get the tumor out without then having to go chase it while it's floating around in the bladder?

David D'Andrea: Yeah. Thank you for this question. This is indeed one critical point, and it's also the limitation of the en-bloc to too large tumors. What I usually prefer to do is to use a basket and grab the base of the tumor, which is the most solid part. And there's a good grip and then you can extract also the tumor through the sheath. What you see when you do an en-bloc, even if it's a three- or four-centimeter papillary tumor, while during the en-bloc resection, you're removing the vascularization of the tumor. Also, this exophytic part tends to get smaller. So the three centimeters is always given as a limit, but in good patients also with large papillary parts, even up to four centimeters, you can go safely as this part will shrink immediately after the resection.

Ashish Kamat: Excellent points. Again, David, in the interest of time, we'll wrap it up, but thank you so much for taking the time and spending it with us today.

David D'Andrea: Yeah. Thank you. Thank you for the invitation. It was great. You too.