Latest / Behind The Knife: The Surgery Podcast / Journal Review in Surgical Oncology: Melanoma
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- BTK Surgical Oncology Journal Review - Melanoma - Audio === [00:00:00] Hi everyone. Welcome back to another journal article Review with your surgical oncology team. Our whole team can make it today due to conflicting schedules, but we look forward to having them next time. Let's start out with some quick introductions. I'm Joe Broderick. I'm a research resident at Brooke Ming Medical Center. I'm Galen G. I'm also a research resident at Brooke Harboring Medical Center. I'm Tim Breland. I'm a surgical oncologist at Brook Army Medical Center. Okay, let's get started. Today we're covering two trials in melanoma, the Preto and Medina trial, both of which investigate the efficacy of neoadjuvant treatment and macroscopic nodal melanoma. That's stage three B through D disease, as well as the use of response driven treatment plans. The earlier landmark trials, MST one and MST two were covered in great BTK episode released in September, 2022 by our UT Southwestern team. These trials established a treatment approach for intermediate thickness melanoma with a positive said known lymph node biopsy. Showing that while these patients benefited from sinone lymph node biopsy, they don't necessarily need a [00:01:00] completion lymph node dissection. So with that background, Dr. Reland, can you start us off by setting the stage for these two trials? Yeah. So, you know, a lot of things have changed in melanoma because of effective medical therapy. So when I was the resident, it was like if you had node positive melanoma or god forbid, metastatic melanoma, it was just a death sentence. There was really not much that could be done. Then with the introduction of ipilimumab and then other checkpoint inhibitors, the melanoma landscape just totally changed. So now when you see a patient with advanced melanoma, you say, well, hopefully you respond to immunotherapy. If you do, then you're gonna do great. And the question then becomes, and this is becoming cross a number of different malignancies, is what is the role of surgery for these patients? If you have an outstanding response to immunotherapy. Maybe you're cured and surgery's really not gonna help you. And so that's, I think what these trials are trying to catch up to and address is that, you know, all of a sudden we have this miracle [00:02:00] therapy of immunotherapy. I shouldn't use that term 'cause it doesn't work for everybody. The question is, when it works, it works incredibly well. I am very loath to ever use the word cure in the world of surgical oncology. But with immunotherapy, when you respond really well, there are a subset of patients that are truly cured. And so even if you present with bulky lymph node disease, if it all gets totally wiped out with immunotherapy, then why are we operating? Are we actually helping anyone by operating? And just like with. MST two where we saw that sometimes less surgery doesn't actually hurt the patient. Now you factor in, well they had a great response to immunotherapy. What are we really doing by doing a lymph node dissection and potentially adding morbidity to these patients? And I think a lot of the residents probably do a lot of breast surgery. And we're going away more and more from doing axillary surgery in the world of breast. It's even more important in the world of [00:03:00] melanoma. 'cause you're talking about groin dissections. So in axillary dissection, sure there's some morbidity, there's some pain, there's a risk of arms quality, but the rate of lymphedema of the lower extremity and the wound complications of a groin dissection are much, much higher. So the push to get away from dissections is even stronger in melanoma than it is in breast. And so that's kind of where we've landed on these trials of like, do we really need to do a groin dissection just because the patient presented with bulky disease? If they respond to checkpoint inhibitors. That if they respond being the key part. Thanks, Dr. Gland with that galin, do you think you can tell us a little bit about how checkpoint inhibitors work? Yeah, definitely. One of the defining features of melanoma is with many cancers is its ability to evade the immune system. So tumor cells can do this by exploiting the immune system's, natural breaks, known as immune checkpoints, which normally serve to keep T-cell activation under control. By activating these checkpoints, the tumor cells can [00:04:00] essentially turn the T cells off, preventing them from recognizing and killing the cancer cells. The two major checkpoints that we target in melanoma are CTLA four and PD one and PD L one. Checkpoint inhibitors block these breaks preventing the tumor from shutting down the immune system response. This allows the T-cell to not only attack the tumor more effectively, but also to proliferate and amplify the overall anti-tumor response being developed. Joe, can you tell us a little about what's unique in using these drugs before surgery in the adjuvant setting? Yeah, for sure. Historically, checkpoint inhibitors were given after surgery in the adjuvant setting when most of the tumor has been removed. The potential issue is that with so little tumor remaining, there's less material for the immune system to recognize and build A strong, durable T cell response to new adjuvant therapy flips that model. By introducing checkpoint inhibitors while the tumor is still in place, you expose the immune system to a much larger pool of bands.[00:05:00] This is theorized lead to a more robust T-cell priming greater clinical expansion, and really ultimately a stronger systemic response. The idea is that this upfront activation will shrink the tumor before surgery and it'll set 'em up for better long-term control of metastatic disease. So now that we have some background, let's get started with these trials. Go ahead, Galen. Earlier trials prior to Paeda suggested that neoadjuvant checkpoint inhibitors such as ipilimumab and nivolumab can induce high rates of pathologic response in patients with macroscopic no melanoma. So in other words, these tumors were resected after neoadjuvant therapy in a large proportion showed minimal or no viral tumor on certain pathology. So this ForSight concept, uh, keeping the tumor in place during immunotherapy, it may end up generating stronger, more effective anti-tumor response. Although these were small studies patients with a major pathologic response, also associated with markedly improved occurrence free survival [00:06:00] compared to the historical expectations at the same time. Other earlier phase work had explored avoiding upfront therapeutic lymph node dissections, and these studies shown that the index lymph node, the largest lymph node involved in the basin, can serve as a reliable surrogate for assessing the overall nodal pathologic response. So kind of putting it all together, there seemed questions that these trials of to answer first, can new adjuvant immunotherapy improve prognosis in patients with macular ectopic nodal melanoma? Second patient does have a strong pathologic response. Is there an opportunity there to deescalate surgery or adjective therapies? And then lastly again, the index lymph node reliably measure the response and guide subsequent treatment decisions. So with these questions in mind, Joe, can you get us started with talking about the pre-up trial? Just real quick before you guys do that, hopefully you guys understand some of the kind of background of that index lymph node question, right? So in breast. [00:07:00] We have what's called the targeted lymph node dissection, where you clip the node, you do a biopsy, you clip the node up front, give them neoadjuvant, and then you take that clip node out and then a sentinel node as well. And that basically has shown that if you take those two out and they're negative, then the rest of the aela is negative. And so there was sort of that historical context for the idea to then be pushed into melanoma. So I don't know that people would've trusted it as much if we didn't have all that history with breast. Okay. Yeah, it makes sense. Thanks Dr. Reeling. So let's get started with the PRETO trial. Preto was a phase two trial investigating the safety and efficacy of neoadjuvant ipi and nivo for patients with Mastro nodal melanoma, along with the feasibility of using this index lymph node to guide the subsequent management. This builds only theum NEO trial, which determined the optimal dosing and schedule for neoadjuvant ipi nivo, and showed that this regimen could produce a very high pathological response rate. So Galin, can you tell [00:08:00] us the trial design? Yeah, definitely. So Prado's prospective single arm extension cohort from that Opus and NEO trial. It included patients with resectable, macroscopic, nodal melanoma. All patients underwent the marking of the index lymph node de enrollment, followed by two cycles of epi nivo with the index lymph node resection at week six. Subsequent treatment was then determined based off of that pathologic response found in that index lymph node. So I grouped patients into one of three categories, either a major response, a partial response, or a non-response. Joe, can you explain the SCOOP students in the primary endpoints of that trial? Sure thing. The major pathological response group, patients with 10% or less residual viable tumor on pathology. Got no further treatment and just underwent surveillance, so they had no lymph, no resection, and they didn't receive any adjuvant therapy. The partial pathological response group, that was patients with 10 to 50% [00:09:00] residual tumor on path. They underwent a therapeutic lymph node dissection, but got no adjuvant therapy. Then the pathological non-response group, so that's patients with greater than 50% residual viable tumor. They got the full deal. I had therapeutic lymph, no dissection, avan therapy, and even possible radiotherapy. The trial overall had two primary endpoints. One was the pathological response rate, and the other was 24 month recurrence-free survival. Perfect. Thanks, Jill. So in summary, this is a response directed deescalation based off the tumor response that we're seeing in the index lymph node. And also we're gonna investigate the safety and the efficacy of neoadjuvant ipi nivo. So let's start working through some of the results. In the 99 patients that were enrolled, 90% were able to receive the plan. Two cycles of neoadjuvant ipi nivo, and only 10% had received one cycle due to adverse events. In total, 22% of patients experience a grade grade, grade four adverse event, [00:10:00] majority being related to a mutilated he or diarrhea and colitis. No treatment related deaths were observed in the cohort. And just a comment again on historical context there. So IPI is a CTLA four inhibitor, nivo PD one. So the IPI came out first. It was more effective than any drug had ever been in the setting of metastatic melanoma. Very toxic. And what I mean by that is that it's not that all the patients had toxicity, which is kind of what you see with chemotherapy. What you see with immunotherapy is a little bit different. It's like only some patients have toxicity, but the ones that do have a lot of toxicity. So in the initial IPI trial, there were patients that died of colitis because nobody really knew how to manage it. And so that was kind of a scary drug. Then they gave both and they found that it worked better, but there was even more toxicity. So that ipi nivo combination had a lot of toxicity when it was first being used. You know, it was probably what, 70 years ago. And then when the PD [00:11:00] ones came out as single agent, most people sort of preferred just giving that because the toxicity was a little less severe, even though people still had autoimmune toxicities. But it just wasn't quite as scary. So then putting back the IPI nivo together has always been like, well, we'll do that. If the single agent PD one doesn't work, we'll add the CTLA four, but we know that the toxicity is gonna be worse. So these adverse event numbers are really pretty promising. You know, there's only 10% had to stop. Now, granted it's only two cycles, but only 10% had a stop here to adverse events and only 22% experience a grade three, four. Those numbers are significantly better than the early trials with these, and that's probably because. Now medical oncologists know how to recognize these and treat them very quickly. So as soon as the patient presents with some diarrhea, they start 'em on steroids. That kind of a thing. I think IPI Nivo is considered a very scary combination. This trial shows that really, it's not too bad, but another very important thing is it's only two cycles. So [00:12:00] it's not like neoadjuvant for breast where they get six months of therapy, you know, before you go take that index. No, you're talking just two cycles. And again, that speaks to the biologic of, of immunotherapies when it works. A lot of times it works right away, like one cycle and boom, the disease has disappear and it may not disappear radiographically, but the lymph node may not shrink, but all the cells inside are dead kind of a thing. And so it's really a remarkable drug and really has changed the face of oncology in general. These immunotherapies have. So just so a couple things to highlight is that it's only two cycles. It's very quick. There are three weeks cycles typically. So you're talking about. Six weeks of neoadjuvant therapy as opposed to six months. When it works, it works really quickly and we as a field have gotten a lot better at using 'em. Toxicity, not too crazy in these trials. Yeah, thanks Dr. Breland. Kinda like you said, the neoadjuvant immunotherapy was really well tolerated in this trial. Now, Galen, can you tell us about the pathological response found on the index left node? So [00:13:00] the researchers were able to demonstrate high feasibility of performing the index lymph node dissection as 96% of patients were able to have that node retrieved. And while only 45% of them demonstrated a radiographic response, 72% had a significant pathologic response. So if we break that down a little bit more, 49% had a pathologically complete response. 12% had a near complete response, and 11% had a powerful response. And then the last 21% were non-responder. Just really remarkable. Two cycles of therapy, half the patient's complete pathological response. You don't see that anywhere else. You don't see that ever with chemo. You know, it's just, these are unbelievable numbers. Yeah. Even though the radiological response wasn't a reliable indicator, the almost three quarters of patients had a pathological response. Allowing deescalation with avan treatment is like Dr. Er said, truly amazing. Exactly, and this is important as [00:14:00] 84% of the patients that ended up in regarding a total lymph node dissection, experienced surgery related adverse events compared to the 46 that underwent the index node dissection only. So even more on patient related outcomes, those undergoing index lymph node dissection compared to the therapeutic lymph node dissection, which are significantly better, global and physical functioning, as well as quality of life mentors in 12 weeks with some of those improvements lasting even two years post-op. Yeah, that's an important point, man. Demonstrates how foregoing a therapeutic lymph node dissection really does make a difference for patients. Gillin, what were the survival outcomes after immediate follow-up of 28.1 months? The estimated 20 point month recurrence free survival for the entire cohort was 85%, but the event free survival of 80% distant metastases, free survival of 89%, and overall survival of 95%. Let's break it down a little bit farther. In the first group, the major pathologic responders, they did not undergo the therapeutic lymph node dissection or adjuvant therapy. Their 24 months where per two survival was 93% and their [00:15:00] distant metastases, free survival was 98%. In our second group, the partial pathologic responders, they underwent the therapeutic lymph node dissection, but did not receive adjuvant therapy. Their 24 months of recurrence survival was 64%, and distant metastasis free survival was 64% as well. Then lastly, in our third group, the pathologic non-responders who underwent the escalation therapeutic lymph node dissection in adjuvant therapy, their 24 months survival was 71%, and distant metastas free survival was 76%. So summing it all up, those with the major pathologic fonts had exceptionally better outcomes even without the therapeutic left, no dissection or the adjuvant therapy. Those that are partial responders, they had a worse overall response with deescalation compared to those non-responders who did undergo escalation, uh, adjuvant therapy and therapy to bi dissection. Yeah, I would sum that up, and I hate to say this as a surgical oncologist, but I would sum that up as [00:16:00] surgery doesn't actually do that much, and effective medical therapy does so much, which has been a theme of my voice on this podcast for years. We love to do surgery and it, it helps some, but you look at the patients who got two cycles, two soft therapy and nothing else. And if they had a strong response, they had a 2% chance of developing metastatic disease in the next two years. And that's what they die of, right? That's what patients care, they wanna live. They don't want to have metastatic disease, 2% chance of recurrence. Whereas if they had a partial response and got surgery, but no more medical therapy. They now had a 36% response. So that group actually did the worst, the ones that did not get additional medical therapy and they still got the surgery that we can offer. So it's not that surgery does nothing, it helps clean up the mess. But they had effective medical therapy Trump surgery 10 times outta 10. That makes sense. Dr. Reland it born out. Some significant limitations to this study. So first Preto is a single arm phase two trial with no randomization or control group. All [00:17:00] the comparisons are indirect, and these results therefore are hypothesis gen generating only sample size is small, uh, with even smaller subgroups, only 11 patients in the partial non-responder, for example. And another question is whether the index left truly represents the pathologic response, the entire nodal basin. So the heterogeneity of the response remains a concern for patients who did not undergo surgery that remains unknown. Finally longer follow up, follow along. Trials are definitely needed. Thanks Galen. We should hopefully see some updated long-term results from Preto in the near future, as well as some early findings of Ms LT three, which builds off this trial and will answer these exact questions. Perfect. Nelson's transition, our next trial in the Dina trial. This sought to show whether or not neoadjuvant immunotherapy should be the new standard of care for macroscopic, nodal melanoma. Joe, can you introduce this trial for us? Yeah, will do. As we previously [00:18:00] discussed earlier, phase two trials had suggested that neoadjuvant administration of immunotherapy improves event-free survival when compared to just adjuvant administration with the best results seen with the combination regimen. Athe Nivo, as Dr. Reland discussed, the NAA trial was a multicenter international phase three trial that randomly assigned patients. With resectable, macroscopic stage three melanoma to receive either neoadjuvant or adjuvant immune checkpoint inhibition. So we're comparing the neoadjuvant regiment to just the adjuvant regiment. Macroscopic disease was defined as pathologically proven in leuk novo metastasis that was palpable, positive according to pet or measurable on imaging. Yeah. Just a comment on the macroscopic. So this, again, so much of this stuff, breast cancers is so much more common and this ular management stuff is so applicable between the two diseases. One of the controversies in breast for a while [00:19:00] was, are we defining a clinically positive node as that which can be felt on exam or seen on ultrasound? 'cause some centers were doing ultrasound on everybody. Some weren't. So now it's pushed more towards, most breast surgeons are getting an axillary ultrasound anytime they're diagnosed with a breast cancer. So most breast imaging centers, if they diagnose breast cancer, they're automatically gonna ultrasound the axilla, and then they may find a node that has a thickened cortex, looks abnormal, but would never be felt on exam, particularly with an obese patient. So should we be doing that with melanoma, I think is an open question right now. I lean towards, yes. Because now that we have something to do with that information, I want it. Right? So if you have no treatment for a node positive patient, why diagnose it? Just do the sentinel node and figure it out later, right? But now we have meaningful treatment for these patients. So you want to know that information when you can. The question is, should we be hitting patients with a slightly thickened cortex and a needle positive lymph node with [00:20:00] ipi nivo? That's kind of a, a more subtle question, but. I think knowing about these lymph nodes upfront, now we can actually do something about it, but I think more places are moving towards either more PET scans or more nodal basin ultrasounds upfront, because the reality in America is half our patients are obese. It's really hard to feel in node sometimes in a obese patient and their groin or in their axilla. So imaging can be help. So I like the way they, they classified this, they didn't say palpable positive node. They said palpable or enlarged on imaging, because that is a much more practical definition than what often were used in the early trials of breast cancer, where they just talked about clinically positive nodes, which most people interpreted as palpable first. Thank you, Dr. Breland. Joe, can you tell us about the treatment regimens? Yeah, sure. Patients in the neoadjuvant group received two cycles of IPI nivo, followed by a therapeutic limb dissection, and if applicable, resection of in-transit metastases. Patients who had a locally assessed [00:21:00] major pathological response didn't receive any adjuvant treatment, and patients who had a partial pathological response or a pathological now response received adjuvant VRAF targeted therapy for 46 weeks if their melanoma had a BAF mutation. Or received an additional 11 cycles of adjuvant nivo every four weeks. If the melanoma was BRAF wildtype, patients in the adjuvant group underwent a therapeutic lymph dissection in week zero, followed by 12 cycles of adjuvant nivo every four weeks, starting between week six and 12. Just a quick mention for those that might be confused by the BRAF thing we've been talking about immunotherapy, now we're thrown in BAF. So if about 60% of melanomas will be BRAF, FB 600 mutated. Those patients will respond to other targeted therapies that you know is roughly called BA or BRAF MEK inhibition. So for patients who don't respond to immunotherapy for 60% of them, there is another option. So this trial is saying, listen, if you didn't respond to [00:22:00] immunotherapy, it would be malpractice to keep you on immunotherapy if you had this other effective therapy available. So they just moved the adjuvant arm to BA directed therapy. If patients have BRAF mutated mutation, if they don't have a BA mutation, they really stuck with immunotherapy and nothing else. So to summarize, we have a population of macroscopic, nodal melanoma patients all undergoing at therapeutic lymph node dissection that are divided into two arms. The adjuvant arm underwent response directed systemic therapy and the standard of care arm where all patients got upfront surgery and adjuvant systemic therapy. So Joe, can you tell us what the primary secondary endpoints were in, start off with some of the results? Yeah, so the primary endpoint was event-free survival defined as time from randomization to the progression of to unresectable melanoma before surgery, disease, recurrence, or death due to melanoma or treatment. Secondary endpoints include pathological response, safety measures, and a few others that weren't reported in this publication. For reasons we'll kind of discuss later, a total [00:23:00] of 4 23 patients underwent randomization. All the neoadjuvant patients started systemic therapy with roughly 94% receiving the plan. Two cycles. At B Nivo therapeutic lymph node dissection was performed at about 93% of patients in the neoadjuvant group and in the adjuvant group, 98% of patients underwent their therapeutic lymph node dissection. Awesome. Thank you. So in our neoadjuvant arm, nearly all the patients that started dipping nivo were able to complete it less than 5%, not proceeding to surgery. Really demonstrating the feasibility in this neoadjuvant approach. Can you tell us a little bit about the efficacy of this? Yeah, so this trial was ultimately published after the first interim analysis given the overwhelming positive results for event-free survival. The estimated 12 month event-free survival is 83.7% in the neoadjuvant group versus 57.2% in the adjuvant group. These are truly paradigm changing results with only about 20% of patients experiencing an event at [00:24:00] 12 months in the Neoadjuvant group. Versus almost half of patients experiencing an event at 12 months in the adjuvant group. Now, Galin, can you break it down a little bit further by the pathological response? Yeah. So in the neoadjuvant group, all patients had received at least one dose of neoadjuvant therapy to be assessed for pathologic response. So 59% had a major pathologic response and 47.2% of total patients having a pathologically complete response. So no residual tumor. 8% of patients had a partial pathologic response. About 26 had a pathologic non-response, and then 2.4% have progression prior to surgery. So the eventatory survival at 12 months was 95% for the major pathologic response. 76% for the partial pathologic response at 57%. So the non responders, thanks Galen, so almost no patients who had a major pathological response and did not undergo adjuvant therapy. Had an event at 12 months. [00:25:00] Versus nearly half the patients who had a pathological non-response and did receive adjuvant therapy had an event at 12 months. This really highlights how prognostic treatment response can be and how much tumor biology really matters. Yeah, very similar to the other trial. A couple just distinctions for everybody in these trials. This was a phase three trial was larger. Right. So people are gonna trust the results a little bit more. The PRETO trial. It was a phase two trial, but as a surgeon and as a practitioner, I think it's a better trial. Like that's the question I want answered is whether or not you need a therapeutic lymph node dissection. This trial didn't answer that question, so it said if you have a major pathologic response, you're gonna do better. Okay. That's not shocking. But it does. I think what shocked people about this trial was two cycles of immunotherapy and that many patients, you know, 60% roughly had a pathologic complete response. So that was like the huge takeaway from this [00:26:00] trial that I think was, like you said, kind of paradigm shifting. The other thing it said, which everyone kind of suspected, is that neoadjuvant immunotherapy is better. So you should give it upfront, which again makes you think. I should try to diagnose as advanced the stage as I can to justify neoadjuvant in some ways. Not that you want the patients to have advanced stage, but if they have a positive lymph node, you want to know about it. So make sure you're doing a thorough nodal exam and then get an ultrasound or a pet and have a high suspicion. So, you know, I think these two trials taken together, neoadjuvant is better. If they have a major pathologic response, they're just gonna do way better, not shocking, right. Then the question that MSLT, he will answer in what Preto sort of answered, but it's only a phase two, so it needs to be confirmed in a larger trial is if you could do a targeted dissection ala breast cancer, right? Like put that node up, do a needle biopsy, leave a clip in that node, give them two cycles of [00:27:00] immunotherapy, and then take that, no doubt, and see what happened. If they had a panel complete response, you're probably done. But I think that until that, you know, until that trial is done, most practitioners are probably gonna keep giving some PD one. So a lot of Med Oncs are gonna finish the year of nivo is kind of what they talk about. Even if they have a pathological response, this data would say, you probably don't even need that. The good thing is that single agent nivo for a lot of patients is so well tolerated that it's not a huge deal minus the financial burden potentially. I think that most people with this data in mind, as soon as the patient has an adverse event, they stop the adjuvant therapy. They say, well, you don't really need it. Probably we'll get to the point where they're not getting that adjuvant therapy. But I think those are, you know, kind of the summary take homes from these two trials. And I think that Ms. LT three will hopefully hammer in all home if it shows similar results to Preto. Thanks, Dr. Rein. Galy, do you wanna finish this up just by discussing the [00:28:00] safety of these treatments? Definitely. So grade three or higher adverse events occur in about half the patients in the neoadjuvant group and only a third of patients in the adjuvant group. Most frequent adverse event were hypothyroidism and adrenal insufficiency, and one patient died in the adjuvant group from pneumonitis caused by nivo, and no treatment related deaths occurred in the neoadjuvant group. Thanks, Galen. So, while neoadjuvant therapy resulted in better event-free survival, it also had higher rates of adverse events relative to the adjuvant group. Which is as to be expected with almost half the patients having grade three or higher events versus a third in the adjuvant group. Now, Galen, Doug, ve already kind of discussed this, but can you briefly go over some of the limitations of this trial? Yeah, so despite the objective superiority of neoadjuvant treatment, these are one year results that are short term, additional followup is going to be needed. It's important to realize that the neoadjuvant arm had double the toxicity of the adjuvant therapy alone arm for grade three and higher adverse events. It's also worth noting that [00:29:00] the treatment approach relies on reliable evaluation of that pathologic response by local pathologist, which may not be available for every institution. And then finally, the DNA included therapeutic lymph, no dissection for both arms in the trial, but as demonstrated in the pato trial is treatment strategy is an evolution right now. So synthesizing different treatment strategies across multiple trials is an ongoing effort that needs more investigation. Thanks, Dylan. So the INDINA trial changed the treatment paradigm for macroscopic nodal melanoma with neoadjuvant therapy suggesting superiority to adjuvant therapy alone in terms of event-free survival for the general surgeon in the community. The takeaway is if you see a patient with macroscopic nodal melanoma, you should be thinking neoadjuvant therapy and get them to a center that can discuss the relevant benefits and downside. These trials still leave. A couple important questions left for further investigation. Can the index lymph node truly be used as a surrogate for disease burden and dictate subsequent therapy [00:30:00] negating the need for a therapeutic lymph dissection? And the other question is, what more can we do for patients who do not have a major pathological response, whose outcomes are kind of still wanting? Yeah, so I think for the residents, just to put it in a clinical context, so a patient presents with clinically positive nodes. The old paradigm was like you would just immediately do a resection with a therapeutic dissection and then put 'em on some kind of adjuvant therapy, but the paradigm has shifted. That patient should get neoadjuvant therapy. That therapy in the light of these trials should probably be a short course of dual agent therapy, and then you should go take out a representative lymph node if they have like grossly matted nodes up front you, you probably could just take out that kind of oftentimes. Even if they respond, those nodes will sort of stay in a Madden ball and you end up almost doing a therapeutic dissection anyway. But you try not to if they don't. Ideally what you need to make sure of is that there's a clip in a node that you know is [00:31:00] positive, right? So how do you do that upfront? You get an ultrasound guided biopsy. You leave a clip, that biopsy comes back positive. Great. They get two cycles of epi nivo. You then go take that note out. Now, again, this is based on phase two data, so the guidelines are sort of wishy-washy, haven't totally caught up, but in practice, this is kind of what I'm doing. Everybody's anticipating the MSLT three trial for now. Standard of care is, we're in this sort of gray area like we were with breast five years ago, where it's like, do you still do a therapeutic dissection? 'cause they had clinically positive nodes up front. I am of the belief that that this is where we're headed. And so I talk to the patients about it. I say the guidelines don't exactly say this, but this is what I think is best. You go take that note out. That note comes back with zero cancer cells in it. In my opinion, they probably don't benefit from a therapeutic dissection. Again, we need that phase three data. They don't have a pathologic complete response. They have a partial response. This is, I think, the difficult area right now [00:32:00] because there is some data from other answers that if you give a more immunotherapy, then maybe they'll continue to respond and maybe they'll get to a more significant response with more immunotherapy. But I think the standard of care right now would be that patient needs a therapeutic dissection, and in my opinion, it should then get some more immunotherapy if they don't respond at all to immunotherapy. Then you're sort of barking up the wrong treaty. Hopefully they have A-B-R-A-F mutation. You can treat 'em that way. There is no doubt to say that that patient doesn't need a therapeutic dissection. Even if they respond to, to other targeted therapies, to braf mek, part of that is the mechanism, right? So braf me those. You know, it's just different. Immunotherapy is different. It uses the immune system and probably when you have a great response, that response lasts longer than anything we've ever seen with normal systemic chemo. I think BRAF mek, it's targeted, but it's more in that kind of realm where they're gonna respond, but eventually they may recur. And so maybe there's more benefit to clearing out those nodes surgically. [00:33:00] And that's all kind of up in the air, big maybe stuff. But I think that's kind of the way I would put it in my head is give the neoadjuvant and then if they have a. Pathologically complete response. Probably don't need anything else. If they have a partial response, nobody really knows what to do. Maybe more immunotherapy, maybe do that dissection down the road. Maybe do it now. You know, I, I don't think you can be faulted either way. If they don't respond at all, you gotta do something different. Thanks, Dr. Brein. I think that's a good ending point for today's episode. Thanks for joining us on Behind the Knife. 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