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E. David Crawford: Hi everyone, my name is E. David Crawford, and welcome to UroToday Crawford's Corner, where we focus on some late-breaking things that happen.

Joining me today is Dr. Seth Lerner, who is a urologist and head of the GU Committee of the Southwest Oncology Group. Seth is from Baylor College in the Scott Department of Urology. The Southwest Oncology Group over the years has contributed a lot to our understanding and management of bladder cancer. We did the studies that basically got BCG approved. We did studies with maintenance therapy with BCG, showing the value of that, and also delved into neoadjuvant chemotherapy prior to cystectomy, showing a benefit for that. The group continued to work on bladder-sparing ideas and procedures. And one of the things that needed to be studied was the extent of surgery and lymph node dissection. And in this week's New England Journal of Medicine, a study was published with Seth as the lead author, and it was entitled "Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer," which I have in front of me. Seth, thanks for joining us to discuss this study and the implications.

Seth Lerner: Yeah, thank you, David. So just by way of a short history, in 2010, when Ian Thompson was the chair of the GU Committee, we were in a regular executive committee meeting, and I had been talking to Bernie Bochner, who frankly had this idea of testing this, or asking this question about extended versus standard. He and I, and there were other people who had trained with Don Skinner, as you know, and Don was a strong proponent of sort of "more is better," so to speak, and had published on this. And we recognized that it was all supported by large retrospective cohort data, but there was no level one evidence really supporting what we were doing. And at the time, there had been randomized trials in other organ site cancers—pancreas, esophagus, gastric—that had similar kind of retrospective cohort data showing the same thing. But when they did their clinical trial, they did not show a benefit to doing an extended node dissection. In fact, in gastric cancer, the outcomes were worse.

So we had a good group of high-volume surgeons, high-volume centers, academic centers, who believed in the equipoise about answering this question. So we designed the trial to simply determine whether or not an extended node dissection would be associated with improved disease-free and overall survival. And so the first patient was in in 2011, last patient was in in 2017. We randomized 592 eligible patients, and we had a median follow-up of 6.1 years in both arms. And some of that was due to a low event rate. And so, this cohort was comprised—the majority were T2, about 70%. Variant histology, I think, was about 10 to 15%. I'll give you the precise number, which is fairly typical of this patient population. I think one of the unique things was that the majority of patients got neoadjuvant chemotherapy, and 87% received standard-of-care neoadjuvant chemotherapy. As David, you pointed out before, SWOG had done a trial demonstrating the benefit of three cycles of MVAC plus cystectomy, one of two trials establishing that as a standard of care.

So the outcome, interestingly, was that there was no benefit in both of those endpoints. The curves are completely overlapping. And we think that there's a number of reasons that there may not be a difference, and probably one of which is the fact that so many patients got neoadjuvant chemotherapy. And the data that we based the statistical assumptions on were largely in the pre-neoadjuvant chemotherapy era. The control patients did a little bit better in both outcomes, about 5% better than the estimates. So we weren't powered to show small differences. We felt like we could handle showing about a 10 to 12% difference. So it's possible that the differences may be smaller, but when you look at those curves, they're completely overlapping.

I think one of the things that's really important for the community to understand is that patients who were randomized to the extended arm had a higher high-grade event rate, so that would be Grade 3, 4, and of course 5, which is mortality. And there was a higher 30-day and 90-day mortality rate in the extended versus the standard arm. So there's no benefit to it and it comes at a cost. And so the conclusion is for patients who meet today, patients who meet the eligibility requirements of the trial, which would've been—which were clinical T2 to T4a, N0 to N2, which essentially is clinically positive nodes in the true pelvis, the predominant urothelial cancer, and of course, curable—the surgeon feels like it's curable. Those patients, there's no role for an extended node dissection. So that's kind of the take-home message.

E. David Crawford: Great. I know what you're talking about with Don Skinner. I was his first fellow and sort of lived through all that "more surgery is better." There's so many different important things that come out. One is, it's nice to see that that many people in the trial got neoadjuvant chemotherapy, because we had been pushing for that and fighting for that a long time, as you well know. That made a difference. And then also the survival rates were pretty good. I guess this has a lot of implications as we go forward. I guess there was a trend in other management other than surgery—radiation, chemotherapy, things like that—would that affect the fields? But all those things are important. I guess the next question is, even, do you really need to do any lymph node dissection at all? Just stop them.

Seth Lerner: Wait a minute. This has been asked by a number of people, and this trial—so I know you know this. If you go back 40 or 50 years during a time when a node dissection was not being done, guess what the local pelvic recurrence rates were? They were in the 30 to 40% range. And the bilateral standard, what we call true pelvis—so external, internal iliac and obturator—when that was introduced, guess what happened? The local pelvic recurrence rate dropped to what it is today, 10 to 15%. And in fact, we saw the same thing in our trial. It was 9% versus 13%. And so, we are not going to go backwards in terms of not doing a node dissection.

E. David Crawford: I'm glad to hear that, because I think that's going to come out. And I guess a couple things are, it helps direct further adjuvant therapy in people that have positive lymph nodes. And then also, part of the Skinner tradition was that in some people with microscopic node disease that you can cure them with a lymph node dissection, but you showed you don't have to do a super aortic lymph node dissection to achieve that.

Seth Lerner: Right. That was really the seminal contribution of Don Skinner, and Ken Steven from Copenhagen also contributed to that. That showed us that patients with pathologic positive lymph nodes had curable disease, and that was in a pre-chemotherapy era. And so, we have patients who are curable with surgery. Obviously, now the paradigm is, if you get neoadjuvant chemotherapy and have a clinical complete response, still about 20% of those at least have residual cancer in the cystectomy specimen despite that. But as you pointed out, I think at the top of this, that a number of groups, including SWOG, are looking at bladder preservation with chemoradiation therapy, or can some of these patients be cured with chemotherapy alone? We've got now EV/pembro coming down the pike. So I think there's just going to be a lot of options for our patients, and frankly, a lot of opportunity to continue our clinical trials asking really important questions in SWOG and the other NCTN groups.

E. David Crawford: Seth, again, I want to congratulate you and compliment SWOG and all the investigators. These are studies that are difficult to do. There's no drugs in them, and there's not a lot of outside funding, other than the SWOG mechanism and the dedication of the surgeons. And this is a landmark study, and we look forward to hearing a lot more from you in the future. Really appreciate it. Thank you.

Seth Lerner: All right. Thanks, David. Good to see you.