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Pat Hensley: Hi, my name is Pat Hensley. I'm a urologic oncologist at the University of Kentucky College of Medicine, and I'd like to welcome you to today's Uro Today presentation and discussion on the role of pelvic lymphadenectomy during radical cystectomy for muscle invasive bladder cancer. I'd like to welcome our two distinguished guests and colleagues here today. First, Seth Lerner, who is a professor of urology at the Baylor College of Medicine in Houston, Texas. And Sia Daneshmand, who is a professor of urology and the SUO Fellowship director at the University of Southern California in LA. Gentlemen, thank you so much for joining us.

Seth Lerner: Thanks, Pat.

Sia Daneshmand: Thank you.

Pat Hensley: Both Dr. Lerner and Dr. Daneshmand are thought leaders and have contributed significantly to the field and our understanding of the role of surgery in advanced bladder cancer. They're members of the International Bladder Cancer Group and serve as the former and current Bladder SWOG GU Committee Chairs. So we're honored to have you with us today. I'd like to kick the discussion off by discussing the role of pelvic lymphadenectomy and radical cystectomy, and lymphadenectomy is a staple and a very important part of our extirpative management of muscle invasive bladder cancer during radical cystectomy, it provides both prognostic information and therapeutic value. So I'd like to start with you, Dr. Lerner, if you would, please provide us with some contemporary definitions of what constitutes a template for an extended node dissection versus a standard.

Seth Lerner: So the standard, at least as we've defined it in the clinical trial, is complete removal of external internal obturator lymph nodes. The obturator fossa should be completely cleaned out, from the pelvic side wall to the bladder, from Cooper's ligament to the common iliac bifurcation. The extended, now, includes bilateral common iliac presacral, the so-called presciatic fossa, and then certain surgeons will take it up as high as to the inferior mesenteric artery, the root of the artery. So that's at least how we define it in the clinical trial.

Pat Hensley: Thanks. Dr. Daneshmand, you've contributed a ton to our understanding of the role of extended lymphadenectomy during radical cystectomy. If you wouldn't mind to just walk me through some of the studies you've been involved in and some of the retrospective literature suggesting that there is a prominent role for an extended pelvic lymphadenectomy during radical cystectomy.

Sia Daneshmand: Yeah, thanks, Pat. I think up to now, with Seth's trial, August 1011, and the German LEA trial, all we had was retrospective data, and our standard has been an extended lymph node dissection, which some people call a superextended lymph node dissection up to the IMA, as Seth pointed out. And there's a lot of retrospective data suggesting that pelvic lymphadenectomy makes a difference in terms of comparisons to more limited dissections, showing that survival is better. But it's all retrospective, right?

We've also done a lot of mapping studies throughout the years showing where the lymph nodes are located. So we do know that of the patients who have positive lymph nodes, 10, up to 20% in some cases, have nodes above the common iliac bifurcation, and even above the IMA. The real question is, are those therapeutic? Can you remove these lymph nodes and really cure the patients without any further therapy? And yes, I would argue the answer has been yes in very select patients who have lymph node only disease, we have shown, without further therapy, that certain patients are actually cured. But those numbers are small and you really needed this prospective study to see whether we're making a difference as a whole.

Pat Hensley: Great, thanks. And that's a perfect segue to the SWOG 1011 trial, which was a phase III surgical randomized controlled trial, randomizing patients to an extended lymphadenectomy versus a standard lymphadenectomy. This is, again, run through SWOG, and Dr. Lerner ran the study. If you wouldn't mind, please provide us with a rationale for the trial, some framework for how the trial was structured, and then some of the key findings.

Seth Lerner: Yeah. Sia laid out the rationale beautifully. There was all this retrospective cohort data that suggested a benefit, but it hadn't really been tested prospectively in a randomized trial. The LEA trial, the German trial, hadn't really gotten underway. And so we felt like it would be really important to be able to say, with a high degree of confidence, that the surgeon did a complete standard or standard plus extended, obviously with a one-to-one randomization. One of the key differences between 1011 and the LEA trial is we allowed neoadjuvant, cisplatin-based neoadjuvant chemotherapy, because SWOG had done the clinical trial demonstrating the benefit of that.

And then I think one of the other cool features about the trial was that it was an intraoperative randomization. So eligibility was clinical T2-4a, predominant urothelial, and 0 to N2, and so they were all registered under that. Then intraoperatively, the surgeons were required to examine the extended template, make sure there was no disease there. If there was an enlarged lymph node, they'd send it for a frozen section. If that frozen section was negative, then they could proceed with randomization. If it was positive, the patient did not get randomized; they didn't go on, then the surgeon would do the appropriate operation. And then we required everybody to submit operative and pathology reports and photos for each case, and so we reviewed all of that. And they also had to be fully credentialed. So each of us had to submit five cases, we had a credentialing committee review. This was a select group, high-volume surgeons, high-volume institutions.

Pat Hensley: Talk to us about some of the results, if you wouldn't mind, just shed light on what's to be presented and what's coming down the pipe.

Seth Lerner: Yeah, we randomized, there were 658 I think registered, we randomized 592, 292 in the extended, 300 in the standard, and six-year follow-up overall, and very similar between the two groups. And the primary endpoint was disease-free survival. We powered it to show a 10 to 12% improvement of extended over standard. And as we've shown now multiple times, the curves are overlapping. There just simply is no difference, both for disease-free survival and overall survival.

Pat Hensley: Can you comment on the rate of adverse events and complications with the two?

Seth Lerner: Yes. So the short version is a higher rate of grade three through five adverse events, higher mortality rate in the extended versus the standard. Some of those are related to VTEs, sepsis, and so it's really hard to... This is very precisely annotated data, and so there is a risk to doing an extended node dissection. And so in the absence of benefit, for the patients who met the eligibility requirements of the trial, I think it's hard to justify the increased toxicity.

Pat Hensley: Well, I want to congratulate you both on your immense contribution to that trial, and I think we can all agree, you provided practice-changing data. Curious as we sit here in 2024, in your practice, is there still a role, even in a subset of high-risk patients perhaps, that you might consider an extended template? And I'll start with you, Dr. Daneshmand.

Sia Daneshmand: Sure. Well, let's make something clear. I think all the patients in the trial were high-risk. They had high-grade muscle-invasive disease, T2 to T4a, plus/minus nodes below the common iliac bifurcation. So these were high-risk patients and varying histology, to some degree, was a lot, but had to be predominantly urothelial. So I think it does answer the big question of whether the extended approach makes a difference overall. But I think there are some potential gaps and things that we can maybe agree on that it doesn't answer.

We don't know in variant histology; we don't know what happens post-neoadjuvant chemotherapy for the patient who had clinical node-positive disease, whether doing additional lymph nodes in that area and really cleaning that up makes a difference. The German trial, although it was underpowered, probably, to answer some of these questions, the LEA trial led by Gschwend, did show a decrease in pelvic lymph node recurrence rates or cancer-specific survival, particularly actually the SWOG-SN11 showed a bit lower pelvic nodal recurrence, is that correct? You just presented.

Seth Lerner: But it's totally opposite of what you would expect.

Sia Daneshmand: I know.

Seth Lerner: You would think that that would be better with extended.

Sia Daneshmand: Well, correct. But we do have better treatments now. We have better systemic treatments. So this is a moving target, right? We are trying to answer a question in a specific time period, and it's a bit of a moving target because we do have... Immunotherapy came along during the SN11 trial, and now of course, we have EV Pembro. So things are, again, in flux and we're going to see. So I still think there's a major role for surgical cure for patients. There's the toxicity of systemic therapies that we need to worry about. Not everybody needs systemic therapies, and I think we need to really start to individualize treatment for patients.

Seth Lerner: There are a lot of patients that are not covered in this trial. I think the three of us would agree. So what do you do with N3 disease or N1 nodes? And I suspect that most of us are probably going after those surgically, that would be an extended node dissection. Or the patient who, even though clinical N1, N2 were included in the trial, if you've got persistent measurable disease in the pelvis, I suspect that most of us are probably going to go up at least another level, rather than leave positive nodes behind. But that's not high-level evidence, that's using clinical judgment.

Pat Hensley: Maybe Dr. Daneshmand, if you could comment to what degree are we curing a fraction of patients with surgery alone who might have clinical node-positive disease?

Sia Daneshmand: So then we have to go back to the retrospective data, and we have over 700 patients in our database with pathological node-positive disease so we do have a lot of data just at USC alone. From that, we can glean that about a third of the patients actually have five-year survival, recurrence-free survival with positive lymph nodes. It's a remarkable number, a third of the patients who you would think are in the highest-risk category. Now the caveat is that many of those have received additional therapies, but some have not. We have patients with para-aortic pericaval node-positive disease, a small fraction of them, it's less than 10% of them, who are cured by the surgery.

And those are the special patients I think we need to focus on, those whose bladder cancer, for whatever reason, travels through the lymph nodes. And this is an extension of this idea that even up to the renal hilum, for some patients, with neoadjuvant chemotherapy, we've gone back and done a metastasectomy, if you will, on patients who recurred in the nodal basin between the IMA, for instance, because we did extend it, and the renal. Beyond the renal, I really think they have systemic disease. But again, very, very few patients, but I think there is a subset who don't have hematogenous spread and really have lymph node-only disease.

Those patients behave differently. Their disease is more indolent. You see, from scan to scan, their lymph node grew by three millimeters, and we would never operate until we see that slow progression or indolent disease. And then varying histology where perhaps we don't have the same efficacy of systemic therapy, maybe that's a place for more extended node dissection. So I think there are some other questions that need to be answered, but for the most part, we do have our answer, I think today.

Seth Lerner: I suspect that both of us, all three of us, would probably agree that we don't want to go backwards and say no dissection, or I've heard people bring that up. And it's really important to go back decades to a time when they weren't doing lymph node dissections and the local pelvic recurrence rate was 30 to 40%. So, you saw in the data that I presented today, let's say on average about 10%. So what you pointed out at the beginning, a good thorough pelvic standard node dissection also accomplishes local pelvic control. I think we know that patients who have a local pelvic recurrence generally don't have good outcomes. So I think that's another real benefit of the operation.

Pat Hensley: Well, Dr. Daneshmand, Dr. Lerner, I want to thank you both for your enormous contributions specifically to this important topic in bladder cancer management. And I'd like to thank you all for joining us today for this Uro Today session, discussing the role of pelvic lymphadenectomy in radical cystectomy for muscle-invasive bladder cancer, live from AUA 2024 in San Antonio. Thank you.

Seth Lerner: Thanks, Pat. Appreciate it.

Sia Daneshmand: Thank you.