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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 and Cancer Research at MD Anderson Cancer Center in Houston. And it is a pleasure today to welcome Ekaterina Laukhtina, who is a research fellow at the Medical University of Vienna in Austria, Vienna, and also a researcher at the Institute of Urology and Reproductive health in Moscow, Russia. Dr. Laukhtina has been instrumental in leading many efforts when it comes to urethral cancer, even though she is early in her career. And one of the papers and projects that came to our attention was her work along with the multi-center group on urethral recurrence after radical cystectomy for bladder cancer. So we thought we would invite her and hear her thoughts on this. Ekaterina, the stage is yours.

Ekaterina Laukhtina: Thank you very much for the introduction, Professor Kamat, and thank you for having me here today. And thanks a lot for the invitation to talk on this topic, which is understudied from my point of view. It's about urethral recurrence after radical cystectomy for bladder cancer. And it is known that it is quite a rare event and most of the urethral recurrences are detected within the first two postoperative years after radical cystectomy. However, recent major [inaudible 00:01:32] due to the increased use of [inaudible 00:01:37] urinary diversion has questioned the role of prophylactic urethrectomy as well as the risk of urethral recurrence in general and its management. As in the major guidelines today, they do not recommend performing a routine urethrectomy during performing a radical cystectomy. And it also suggests that in selected patients who are at the highest risk for urethral recurrence, urologists could consider avoiding ONB diversion. And for that reason, correct identification of those patients who have the highest risk for urethral recurrence after radical cystectomy is of importance in order to improve their survival outcomes and as well to avoid unnecessary urethrectomy for those who may benefit from that.

And according to AUA guidelines, there are several known risk factors for urethral recurrence after radical cystectomy. And it includes multiple tumors, papillary pattern, carcinoma in situ, tumor at the bladder neck, and prostatic urethra or stromal invasion. However, I would like to stress that the predictive value of each of these risk factors remains quite controversial due to the fact of a lower rate of urethral recurrence reported across the literature. And the further question regarding urethral recurrence is if it actually affects the survival outcome in patients after radical cystectomy?  And this question is still unclear. However, it is interesting that a few studies reported that the presentation with symptomatic urethral recurrence most likely is associated with poor prognosis in those patients compared to patients in whom urethral recurrence was detected using ureteroscopy or cytology, for example.  And this data was supported by a recent publication in the Journal of Urology. But before talking about urethral recurrence and its management, the first question is how to assess patients at risk for urethral recurrence at the stage of preoperative setting and preoperative counseling of patients.

To answer this question, we performed a systematic review and meta-analysis, it was an updated systematic review. Obviously, there were a few done before. We searched for these study patients that reported on urethral recurrence after radical cystectomy for bladder cancer. And finally, we included 21 studies. It was more than 9,000 patients underwent radical cystectomy. I would like to stress that most of the studies had a retrospective design and small sample size. And among our endpoints of interest, there were incidents of urethral recurrence, risk factors, and survival outcomes. And according to our analysis, we found out that a high risk for urethral recurrence was observed in male patients and those patients who underwent non-ONB diversion.  And further, it was also reported for patients with multiple tumors and prostatic urethral or stromal involvement. However, when we are talking about carcinoma in situ and tumor stage, we did not find an association with urethral recurrence.

It's a bit in the contrast to the previous reporting in the published meta-analysis, especially talking about carcinoma in situ, but this difference could be explained due to different statistical approaches and using hazard or risk ratios for statistical analysis. Nevertheless, we go into it a bit further and the next question, actually, is the impact of urethral recurrence on survival outcomes in patients after radical cystectomy. And there were only nine studies that somehow reported, which somehow reported the association of urethral recurrence with overall survival or cancer-specific survival. So five studies did not find any significant differences in overall survival between patients who experienced urethral recurrence compared to those who did not experience and the same results were found for cancer-specific survival. While I would like to stress again, the fact that patients who were presented with symptomatic urethral recurrence had worse survival outcomes compared to those who were diagnosed by cytology or ureteroscopy.

And the next question that I would like to highlight and stress is the diagnosis of urethral recurrence, as well as the surveillance protocol, were highly and poorly reported and actually highly heterogeneous among the status, such that some of the statuses reported the clinical formula, so that means based on the presence of symptoms only, while other ones reported according to ureteroscopy or cytology in most of the cases. So in making a conclusion of our systematic review meta-analysis we suppose that male patients especially those treated with non-ONB diversion as well as patients with prostatic involvement or multifocal tumors seem to be at the highest risk for urethral recurrence after radical cystectomy for bladder cancer. However, patients with urethral recurrence did not demonstrate significantly worse survival outcomes.

However, we highly believe that risk-adjusted standardized surveillance protocols are needed, and they should be implemented into clinical practice at this stage after radical cystectomy. And there is possible suggested risk stratification included for these criteria such as a multifocal tumor, prostatic involvement, bladder neck involvement, and carcinoma in situ(CIS).  And based on these risk stratifications, patients could be stratified in low- or high-risk. So for example, a patient with at least one criteria could go into the high-risk group. And based on this risk stratification urologists could further consider different management of the urethra at the time of radical cystectomy.  For example, performing immediate urethrectomy or after radical cystectomy, for example, stage uretherectomy, as well as choosing the appropriate surveillance protocols for these patients and further, also the management of urethral recurrence, if it occurs.

And I would like to finish my talk today with a few main take-home messages.  First of all, indeed, nowadays there is a lack of evidence on the topic of urethral recurrence after radical cystectomy for bladder cancer. However, definitely being aware of this problem among urologists and oncologists is necessary to improve the postoperative management and survival of bladder cancer patients. And additionally, we highly believe that risk stratification based on several tumor factors, risk factors can help identify each patient's individual risk for urethral recurrence. That brings me to the end of my presentation and I would be happy to continue to discuss with you, Professor Kamat and also to know your opinion regarding this quite important question. Thank you.

Ashish Kamat: Thank you so much.  As you alluded to, it is a very important question, but one that is often not recognized by people taking care of patients with bladder cancer. And in fact, in radical cystectomy specimens, the incidence of prostatic urethral involvement and prostatic involvement with urethral cancer is often underreported, because the pathologist is not aware of the need to actually look at the prostatic urethra in as much detail as we would like them to. So all the points that you raise, your review provides a really good addition to the literature. I do want to highlight a few things. Number one, obviously knowing which patients are at high risk versus those not at high risk of having a potential urethral recurrence is also driven by the management of these patients, as far as the choice of diversion. Would you like to comment a little bit on the utility for example, of the frozen section at the time of radical cystectomy?

Ekaterina Laukhtina: Yeah, exactly. That's a very good point. Thank you for raising this. And actually, we performed another meta-analysis that was focused on the frozen section. And we found out that, actually the frozen section at the time of radical cystectomy, talking about urethral, the frozen section, we found out that sensitivity was around 83% and specificity was around 95%. So the frozen section seems to be a really useful tool for finding those patients who could benefit from immediate urethrectomy. However, there is literature that the frozen section could be omitted, especially in that patient when non-ONB diversion is planned. But nevertheless, in the case of planned ONB, the frozen section might help ensure a cancer-free anastomosis. And especially in the case of risk factors, the intraoperative frozen section can help determine the real need for immediate versus stage urethrectomy versus no urethrectomy at all.

Ashish Kamat: Yes. And I think the main benefit of a frozen section, as you mentioned, is in patients who are considering orthotopic neobladder, but I would definitely not exclude any patient from an orthotopic neobladder just based on the risk stratification. So the risk stratification helps us counsel the patients preoperatively as to their likelihood of having a positive frozen section, but the positive frozen section can guide us because you can always do another section so long as you have healthy urethra and continue on with the orthotopic neobladder. The other point I want to raise is that we and others used to do immediate ureterectomy if you had a positive margin at the frozen section, but nowadays with ERAS pathways and the way radical cystectomy patients go home in three or four days, doing a urethrectomy at the same time makes it very hard for the patient to ambulate, recover.

And we've found that delaying the urethrectomy to six weeks, eight weeks, even 12 weeks does not affect the outcomes when it comes to the survival of the patient at all. And it actually is much easier for the patient. So unless there is an actual gross tumor at the margin, which we should be very aware of, it is something that should definitely have been picked up preoperatively. But if there is only a positive, frozen section margin, the recommendation would be to remove as much urethra as you can from within the pelvis, but save the actual urethrectomy for another date, which could be anywhere between eight to 12 weeks after surgery, after the patient is recovered because it's a same-day surgery, the patient goes home the same day. It is much, much easier for them to tolerate. Has that been your practice in Europe as well?

Ekaterina Laukhtina: Yes, I would say in Europe it is different between the centers and between the countries, but definitely you raise a very good point again. A urethrectomy could be postponed as a secondary procedure and it was shown in a few studies without affecting actually the survival outcomes. And it could be postponed more than six weeks after radical cystectomy.  But in one of the studies, it was shown that the real survival benefit of prophylactic urethrectomy is only in those patients actually at the highest risk of urethral recurrence. And in those studies, it was multiple tumors and contaminant carcinoma in situ. So I guess patients at the highest risk could benefit from immediate urethrectomy. Otherwise, in other patients, it could be safely performed with a staged and delayed urethrectomy.

Ashish Kamat: Right, and personalized medicine is very critical. So these are general guidelines and general recommendations that we make to our patients, but each patient needs to have informed decision making with a discussion about his specific case and risk factors. This has been great. Thank you so much for taking the time. In closing, I want to give you the last thought, any last thoughts on this topic that you want to share with the audience, any ongoing research that you are involved in, any new publications coming out that you would like to highlight?

Ekaterina Laukhtina: Yeah. Thank you. So I would like to first summon up that we highly believe that to increase awareness of urethrectomy, urethral recurrence, and all these problems, the need for a dedicated follow-up is warranted and decision-making protocols, standardized surveillance protocols should be really developed, implemented in clinical practice. And actually, recently with YAO, Young Academic Urologists in the European Association of Urology group, we are now working on a new systematic review that will be more focused exactly on surveillance and on comparing different urethrectomy approaches. And probably we will come out with a suggested algorithm for decision-making in those patients. But in general, definitely we believe and hope that these studies, these systematic reviews will help to bring attention to this question for the urological community. And thank you very much for the invitation. I do appreciate it a lot. Thank you

Ashish Kamat: It was our pleasure. Thank you for joining us.