Transcript of Does Removing Lymph Nodes During a Radical Cystectomy Lead to Better Outcomes?

August 2, 2023

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Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it, BCAN, producers of this podcast. This podcast is sponsored by the Seagen Astellas Alliance. I’m pleased to welcome today’s guest, Dr. Seth Lerner. Dr. Lerner is a professor of urology and holds the Beth and Dave Swam chair in urologic oncology in the Scott Department of Urology at Baylor College of Medicine. He’s also director of Urologic Oncology and the Multidisciplinary Bladder Cancer Program and faculty group practice medical director for the urology clinic. And he also serves on both the BCAN Board of Directors and the BCAN Scientific Advisory Board. Dr. Lerner, thanks for joining our podcast once again.

Dr. Seth Lerner:

Yeah, thanks, Rick. Good to talk to you.

Rick Bangs:

So, you recently presented some results in a meeting, which you and I would know as ASCO or the American Society of Clinical Oncologists, and it was about a trial that you led that sought to answer a longstanding question in the bladder cancer community on the extent of lymph node removal during radical cystectomy. And I have to provide a disclaimer. I was the patient advocate for your trial. So, I thought we could start with a little bit of an understanding of what are lymph nodes and why are they important in bladder cancer?

Dr. Seth Lerner

Sure. Well, lymph nodes are a very important part of our normal immune surveillance. But in the context of cancer, if cancer cells get outside the bladder, they can travel to the draining lymph nodes and get trapped there. And that’s what we know as lymph node metastasis. So, we know exactly where they are anatomically, we know where to look for them on CT scan, and we know which lymph nodes are the most likely place to find metastatic disease when we’re doing surgery for muscle invasive bladder cancer.

Rick Bangs:

Okay. And so, tell us a little bit about the study. What questions did you want to answer, and for what patients would this be applicable?

Dr. Seth Lerner:

So, for decades, probably dating back to the 1940s-1950s, when surgeons started doing what we call a lymph node dissection or a pelvic lymphadenectomy, when we were doing cystectomy for bladder cancer, we found that we could identify patients with lymph node metastasis, and that by removing those lymph nodes, dramatically reduced the recurrence of cancer in the pelvis. So, for decades, this has been a really important part of a radical cystectomy. In part, that’s why it’s called a radical cystectomy, because it includes a pelvic node dissection. And in the early 80s, my mentor, Don Skinner, at USC, had published a seminal paper saying that a very careful bilateral lymph node dissection, in addition to identifying those patients with pelvic node metastasis, was compatible with potential cure. In other words, if you remove the metastatic disease, that surgery potentially could be curative, and people could survive long term.

He then went on to show data, and others followed suit, that by performing what we now call an extended lymph node dissection, not just targeting the lymph nodes in the true pelvis, but extending it higher up to include the area around the aorta, the main blood vessel that carries blood from the heart to the organs and extremities, removing those additional lymph nodes, or what we refer to as an extended node dissection, helped people live longer. So, it’s been part of our dogma that we should do this so-called extended lymph node dissection in addition to the standard node dissection. But there’s never really been high level evidence to support it. So, the fundamental question that we asked where if you do a more extensive node dissection, is it going to improve both disease-free survival and overall survival?

Rick Bangs:

Excellent. So, now, who funded this study, and who actually conducted it?

Dr. Seth Lerner:

So, this was funded by the National Cancer Institute through one of the cooperative groups, the Southwest Oncology Group, or what we now call SWOG. I’m a member of SWOG. And so, SWOG led the study, but it was really conducted across what we refer to as the A National Cancer Clinical Trials Network or the NCTN. So, there were all the other major cooperative groups participated in this. And we had a total of, I think it was 36 or 37 surgeons at 27 sites across the country and Canada participating in putting patients on this study.

Rick Bangs:

So, it was, in essence, funded by the government using taxpayer dollars?

Dr. Seth Lerner:

Correct.

Rick Bangs:

All right. So, you hinted at this. So previously, the usual care was what?

Dr. Seth Lerner:

So, the standard of care at the time that we started this trial was to do a bilateral standard.. And then we would take that up to include what’s called the common iliac lymph nodes and the presacral lymph nodes. Those are just the anatomic boundaries of the extended node dissection. So, I would argue that the standard of care was really, and we taught this at every opportunity, would be this extended node dissection. And over time, urologic oncologists, who were the ones that do this operation, adopted this. Yeah.

Rick Bangs:

But there wasn’t consistency across all the docs in terms of what they were doing or was-

Dr. Seth Lerner:

Right. Right. Not everybody adopted that. And it’s probably a reflection of training, perhaps a critical review of the literature and interpreting that as, I don’t know that there’s high level evidence supporting doing a more extensive node dissection.

Rick Bangs:

So, there’s some history in other cancers that was helpful in terms of trying to set up the why on this study, beyond the question that we had in bladder cancer. So, what was the history there?

Dr. Seth Lerner:

So, there had been a number of phase three trials that had asked a very similar question of: is there a benefit to a more extensive dive dissection in esophageal cancer, pancreatic cancer, and gastric cancer? And lo and behold, all of them failed to show a benefit to the more extensive node dissection. And actually, in the gastric cancer trial, which was conducted in Japan and published in the New England Journal of Medicine, they actually showed that there may be harm in terms of higher side effects or adverse events associated with a more extensive node dissection.

Rick Bangs:

And was there any evidence in another cancer that the extended lymph node removal was better?

Dr. Seth Lerner:

No, not that I’m aware of.

Rick Bangs:

Okay. All right. And so, people have a tumor and there’s lymph node involvement. So, removing the lymph nodes is important because there might be cancer in there, correct? And it indicates some progression of the disease.

Dr. Seth Lerner:

Right. So, on average, when we are doing this operation for muscle invasive bladder cancer, about 25 to 30% of patients will have cancer detected in the lymph nodes when the pathologist looks at the entire specimen. So, you can imagine that if we don’t remove that, for instance, if we didn’t do a node dissection, well those metastatic deposits in the lymph nodes are going to grow. And that’s one of the primary reasons probably why we see local pelvic recurrence, we see that in up to 15% of patients with positive nodes even when they undergo a node dissection.

So, there’s two fundamental reasons to remove them. One, is we really ratchet down the local pelvic recurrence rate. That’s important, very important. And it allows us to detect those patients that do have spread to the lymph nodes because that puts them at higher risk for progression or recurrence after the surgery. And now we have adjuvant… I’m sorry, we can give immunotherapy after surgery to try to reduce that risk, some patients will even go on to get chemotherapy. But if we didn’t know that, if we didn’t remove the lymph nodes and know that whether or not there was metastatic disease there, we wouldn’t really have that opportunity to identify those high risk patients that offer treatment.

Rick Bangs:

Okay. So, I remember… Shortly after my diagnosis, which would’ve been 2006, but I remember going online and I remember hearing patients talk about the number of lymph nodes that were removed, and it was almost bragging rights. The more that were removed, it almost… The patients were proud that more were removed. And I also remember as part of that conversation, varying numbers.

Dr. Seth Lerner:

Yeah.

Rick Bangs:

And so, how easy or how hard is it to count the number of lymph node removed, and why is there so much variability?

Dr. Seth Lerner:

Yeah. It’s not actually hard to count. So, it just requires a pathologist to be very meticulous in examining all of the tissue that we give them. The surgeon can help by giving them the lymph nodes and what we refer to as packets. So, instead of lumping all of the left sided lymph nodes specimens together, we separated them . We send them different packets, and sometimes those packets can be as many as 9 or 10 different packets. So, Bernie [inaudible 00:11:52], a urological oncologist at Memorial Sloan Catering, did some elegant work showing that presenting the lymph nodes in packets to the pathologist resulted in the pathologist identifying more lymph nodes.

And we also know that the more lymph nodes identified by the pathologist, the higher the probability that they’re going to detect spread of the cancer, lymph node metastasis. And we’ve published on a threshold, in the mid to high 20s. So, we know that the number of lymph nodes identified by the pathologist and the number of lymph node metastasis impact outcome. So, it really requires the pathologist to be very meticulous, examine all the entirety of the specimen, but there’s a lot of things that contribute to variability of lymph node counts.

So, there’s no real bragging rights. I’ve felt all along, and many people agree that the real issue is the complete and thorough removal of all of the potential lymph node bearing tissue is really what impacts outcome.

Rick Bangs:

Okay. All right. So, you did the trial, and we got some results that, as I understand it, are going to change the usual care. So, what’s going to happen now with usual care? What did you find? And when will the new guidelines go into place?

Dr. Seth Lerner:

Good question.  First of all, of the patients got a bilateral standard node dissection. And then because of the one-to-one randomization, half of the people got a more extensive node dissection. So, if you compare the primary outcomes of disease-free survival and overall survival in the half the patients that got the extended plus standard compared to the half that just got the standard, there was no difference in either of those endpoints after six years of follow-up.

So, this trial plus a similar trial that was conducted in Germany that’s been published, which also did not show a benefit to the extended, these two trials, in aggregate, essentially, shut the book on the perceived benefit of an extended node dissection. And really, the standard of care moving forward is a bilateral standard. We don’t need to do an extended node dissection. For patients who undergo a cystectomy that met the eligibility of criteria for the trial, so these were patients with clinical stage T2 to T4, a curable muscle invasive bladder cancer, and they could have had evidence of lymph node metastasis just in the true pelvis on the CT. So, for that patient population, predominant urothelial, which is the most common histologic type, there’s no indication to do a more extensive node dissection.

Rick Bangs:

Okay. All right. So, are there any exceptions to that? Are there cases where you would say, You know what? An removing more lymph nodes is probably indicated here?

Dr. Seth Lerner:

So, one of the things that we did that we claim was fairly innovative and creative in terms of the design of the study was that the first thing that happened during the operation was the surgeon was supposed to do an exploration, particularly in the extended template, and verify that there was no evidence of metastatic disease. If they found an enlarged lymph node that could be metastatic disease, they did what’s called a frozen section. So, they’d remove it, send it to the pathologist while the patient’s asleep. They do what’s called a frozen section, they look at it in the microscope. And if there was cancer there, that patient was not eligible for randomization. All right?

So, those patients are not part of this study. So today, if I got in there and found that similar situation, I’d do an extended node dissection. So, that would be an example where the trial results don’t apply. For patients who have different cell types, so we see much smaller numbers of patients with squamous cell cancer or adenocarcinoma. It doesn’t apply to those patients because they weren’t part of the clinical trial, they weren’t eligible. So, those would be examples of patients for whom you might consider a more extensive node dissection simply because we don’t have the data on them, these trial results don’t apply to them.

Rick Bangs:

Okay. Okay. And so, the people who don’t have squamous and small cell [inaudible 00:17:09] that are adenocarcinoma, those people are normally referred to as urothelial bladder.

Dr. Seth Lerner:

Right, right. Predominant urothelial. Yeah.

Rick Bangs:

Yeah. Okay. So, now, lymph node removal doesn’t come without a cost. There can be side effects. So, what did the study find relative to that? And can you actually mitigate any of these side effects?

Dr. Seth Lerner:

Yeah. So, this was the surprise finding. Our hypothesis was that the more extensive node dissection would not really add significant risk. what we found was that there was a higher risk of what we call grade three, grade four toxicities in the extended arm.

So, the more extensive surgery was associated with a higher risk of grade three, grade four side effects and a higher risk of fatal events at both 30 days and 90 days. Now, the way we classified this was any grade three, grade four event or a fatal event independent of the type of lymph node dissection. In other words, we were not really able to attribute a particular adverse event to the extended node dissection per se. So, these are all events that occur in patients that undergo cystectomy. We know about these, we work very hard to prevent them. Plus, some of those fatal events were actually progression of disease over the 90 day postoperative period. We see that. So, we’re doing a pretty deep dive into this for the… So that we can provide as much detail as possible in the publication.

Rick Bangs:

Okay. And so, grade three and grade four. So grade three is a… That’s a pretty serious side effect. Grade four, I think, if I’m not mistaken, requires hospitalization.

Dr. Seth Lerner:

So, actually, grade four tends to be more on the life-threatening side. So, sepsis would be one of those. Grade three are serious by definition, but almost always manageable.

Rick Bangs:

Yeah.

Dr. Seth Lerner:

And they’re not life-threatening because that’s what grade four can be.

Rick Bangs:

Right. Okay. All right. So now, suppose I’m a patient and I had the extended lymphadenectomy, which means I had more lymph nodes removed, and this was done in the past before we had the findings. So, should I be concerned, and should I do anything because I had more lymph nodes removed?

Dr. Seth Lerner:

Oh, goodness, no. No, no. No concerns whatsoever. If you think about it, that a lot of us have been doing our entire careers. And I’ve been doing this for more than 30 years. And so, has that contributed maybe to a higher incidence, for instance of, we call it lymphedema. So, leg swelling, which can occur after this operation. It’s actually an infrequent event, but it does occur. I can’t sit here and tell you that it’s related to removing more lymph nodes or not. I actually haven’t looked at that. I don’t know that folks have looked at that per se. But no, there’s no real consequence to our health or our immune surveillance by having more lymph nodes removed.

Rick Bangs:

Okay. All right. So, as part of this study, there might be some additional things that you’ve learned and looked at. And as an example, I think you did some work relative to how frequently patients were getting neoadjuvant chemotherapy, who got the radical cystectomy after the chemotherapy. So, anything that you can tell us about other things that you learned as a part of this study?

Dr. Seth Lerner:

Yeah, thank you for bringing that up. At the time, the first patient was enrolled in 2011, and this audience may be aware of that. Really from the early 2000s, we had data from two large randomized clinical trials that patients receiving chemotherapy before this operation, what we call neoadjuvant chemotherapy, plus, cystectomy, did better in patients who just had cystectomy alone. And even though we had that data, the uptake in the urologic oncology community was pretty low, that maybe 10 or 15%. So, we felt like it was important to allow patients to undergo standard of care, neoadjuvant chemotherapy. And it turns out that 57% of the patients got neoadjuvant chemotherapy, and 88% of those got cisplatin standard of care neoadjuvant chemotherapy. No one really during the course of this trial came close to that. So, our multidisciplinary teams, our surgeons had really embraced the evidence.

So, we’ll be able to do some analysis stratified by whether or not patients got neoadjuvant chemotherapy or not, for instance, looking at side effect rates. And we know that chemotherapy is associated with a higher risk of venous thrombotic events. So, we’ll look at that. In addition,  we’ll do a little bit more of a deep dive into the adverse events. But we’re also looking at things like hospital length of stay, operative time, some technical aspects of how the operation was done. These are all pre-specified secondary analysis that will likely be… We will probably include most of that in the primary paper. But the other thing that I’m really excited about is we have tumor samples from probably between 300 and 350 patients, where we’re going to be able to do next generation sequencing for DNA and RNA.

And so, this is really one of the real values of a clinical trial like this, even when it’s doesn’t show a benefit, in this case, to the extended node dissection. We’ve got the 600 patients or so that are enrolled in the trial. We’ve got all this clinical data, all this pathologic data. And we’re going to be analyzing this for a few years to come. So, there’s a lot more that’ll come out of this. We’re very excited about that.

Rick Bangs:

Yeah. So, that tissue does not go to waste. You…

Dr. Seth Lerner:

No, it sure won’t.

Rick Bangs:

Yeah. Yeah. Okay. Any more work that you can predict in this area? Beyond what… You’ve already mentioned some additional studies that are relative to this trial, but any additional studies that might happen in this general space?

Dr. Seth Lerner:

Yeah. From a surgical standpoint, again, this audience may be aware, for instance, that there’s been some randomized trials looking at open versus robotic radical cystectomy. We were required all the surgeons to do open cystectomy in this trial. It was so simply because when we started at robotic, really, there was no reasonable evidence to suggest that robotic would give us equivalent results. And those trials are showing lower blood loss, primarily. And probably a lower wound infection rate. But that requires a very high level of skill to be able to do, to be able to achieve the same outcomes that we do with open surgery. Now, for instance, Neman Naval, MD Anderson, has done a lot of research on patients who present with more advanced disease, so where we know they have lymph node metastasis outside the troop pelvis. So, those patients get treated with chemotherapy, but then we really don’t know what to do with them surgically. Should they have an operation to remove the lymph nodes? Should they have their bladder removed?

And at NEMA, has really been doing some elegant work with that, both from a genomic sequencing standpoint and a clinical trial standpoint. So, that’s an important question to ask and answer. And there’s a hint. I have to be very careful how I phrase this. In our trial, that suggested that patients who had what we call T3, T4, so more deeply invasive cancers and cancers maybe invading the prostate, may have benefited from a more extensive node dissection. So, maybe digging into that a little bit deeper to see if there’s a subpopulation that are undergoing cystectomy that may need a more extensive node dissection. But that would require another trial to ask and answer that question.

Rick Bangs:

Right. Yes. And for listeners who might be interested in the robotic versus open, we had Dr. [inaudible 00:27:29] on a podcast some time ago. So, they may want to check that out. All right. Any final thoughts?

Dr. Seth Lerner:

Well, this is… As Rick knows, on July 1st, I’ve become the new chair of the Genital Urinary Committee and SWOG responsible for JGU cancer trials. I’ve led the Bladder Group for about the last decade. And the National Clinical Trials Network, Cancer Clinical Trials Network of which SWOG is a part of, is uniquely suited to do these kinds of trials. So, they don’t involve a drug, so no pharma company’s going to support it. It’s not a biotech question. So, the National Cancer Institute and the Cooperative Group system is a wonderful place to ask these kinds of surgical questions. And in the bigger picture, do practice changing clinical trials that pharma won’t or can’t do. So, we’re so grateful for the patients and their caregivers that volunteered to participate in this trial, and really got us to this point where we’ve answered this really important surgical question. And just a shout out to all the surgeons who largely had bought into doing an extended node dissection to recognize what we call equipoise, that this question was really important to ask an answer and get this done. So, hats off to everybody.

Rick Bangs:

Yeah. Yeah. I know several who used to do the extended version that were willing to kind of question why they were doing that, because evidence just doesn’t exist. So, you had a great group of surgeons. So Dr. Lerner, I want to thank you for updating us on the important findings from this study. And it helps us understand the extent to which removal of lymph nodes makes the most sense during radical cystectomy. And also, to help us understand how it’s changing the standard of care that bladder cancer patients will receive during a radical cystectomy. If you’d like more information on bladder cancer, please visit the BCAN website, www.bcm.org. In case, people would like to get in touch with you. Dr. Lerner, would you like to share a Twitter handle or some other mechanism?

Dr. Seth Lerner:

Yeah, sure. My Twitter handle is @slerner, that’s my last name, and then @bcmedu1. Sorry, it’s so complicated. But yeah, you can also reach out to us at Baylor College of Medicine, Scott, department of Urology. So, yeah. Rick, thanks so much. This is great, and I’m happy to get to tell this story to your audience.

Rick Bangs:

My pleasure. We really appreciate your time. Just a reminder, if you’d like more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at +1 888-901-2226. That’s all the time we have today. If you like this podcast, never miss an episode by clicking on the subscribe button on your favorite podcasting platform. And rating our podcast helps us reach more people. Please feel free to leave a review as well. Thank you for listening. And we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Lerner.

Dr. Seth Lerner:

Thank you.