Neuroblastoma: Update Course 2016

And we're, I'm going to start off talking a little bit about neuroblastoma. Neuroblastoma, uh, we've made a lot of progress in reducing therapy, uh, all the way down to Jed Nocturne's, uh, study in, in neonates suggesting that they may not need surgery at all. They may need nothing more than observation. But I think that the, the main controversy, at least from my perspective, that still persists is what to do with the high-risk patients. And, uh, those patients present real. Uh, management challenges and especially surgical challenges, and they continue to have a survival rate that's in the 38 to 40% range. So these are very sick, uh, kids that, that need aggressive therapy. Can you advance the slide for me, Mark? Mark Hey Mark, can we, you know the slide advance the slide. OK, so I just wanna, uh, as has been the format here, start with a, a very straightforward case or uh presentation. An 18 month old presents with an abdominal mass noted on a routine exam by the pediatrician, uh, which is frequently the, the presentation for these kids. Vital signs are normal. On exam, has a large central abdominal mass, uh, is mildly anemic. Uh, the urine catecholamines are elevated. And, uh, next slide mark. I can try this network, um. You get a physical exam that shows this uh abdomen on physical exam and a CT scan that looks like the panels on the on the right there. So The question we want to address here is from a surgical standpoint is how important is the completeness of resection of the primary tumor to control both local recurrence as well as patient outcome, and this is something that has been argued back and forth. There is some relatively new data that's just come out within the past year actually supporting both sides of this argument, and so I'll be interested to hear, especially from some of our European colleagues as well as the folks in the room, as to how they would approach this problem. Do we need to do a biopsy only or a minimal resection, or do we have to try to get to uh what looks like the operative field on the right there? And this is the technique described by Mr. Kiely, uh, where you get down to the adventitia and do a complete resection of these large retroperitoneal masses, completely removing as much tumor as possible to achieve as close to 100% resection as you can. So, I'd like to start out just by asking the, the faculty, but also uh pulling the audiences to what, what is your current approach to this kind of a kid? Is this a kid that you would try to be very aggressive, try to get a 90% resection? Is it somebody that you would debulk only the easily resected portions and not be aggressive? Would you refer them to another center, or surgery is not indicated at all? Is this a time of diagnosis or after chemo? Great question. And that actually brings on another question. But let's say gets the standard 5 cycles of chemotherapy and has a residual tumor that has decreased in size but continues to encase the retroperitoneal vasculature, the aorta, the vena cava. So we do an aggressive resection. Same for us. Yeah, I, I think the uh evidence shows that. If there's no evidence of bony disease, bony metastasis, and you have a stage 3 tumor that's isolated to the abdomen, is that what you're talking about here? So that's another question I want to ask. But so, so I'll define that now and say in this, let's, for this purposes of this poll, say that this is a case with a tumor limited to the abdomen without metastatic disease. Yeah, we would try to do a complete resection if possible. Agreed. Yeah, same. Yeah. Would anybody not Oh, I want, I wanna particularly ask our, uh, Dan. Dan, uh we can't hear you unless you're muted. Uh, we would try and see if we would do a 90% resection, not not sacrifice anything. OK. Others like Samir, Samir, yeah, I, I'd try and do it a 90% section as well. I agree with that. All right, uh, Benno. I don't know if Benno's on the phone, it looks like uh we lost our European colleagues, um. So the question, uh, Dan, what would you do in terms of the technique? Would you use Ed Kiley's technique getting into the subadvertibular area of the vessels, or would you go short of that? I would use that technique, and I think that my personal technique is to get wide exposure and actually find the vessels somewhere where you can identify them and then work back in that subadventitial plane peeling the tumor off of the vessels as opposed to working your way through the tumor and finding yourself in the vessels agree with that, yeah. So I think, you know, the, the two ends you gave were debulk versus, yeah, it'll come back. Um, Mark, they can still hear us, right? OK, so, um, I, I would say that 90% resections, so you go from deep bulk to 90%. I, I think maybe the difference might be in, in exactly what Dr. Corn just was sort of talking about is do you completely skeletonize the vessels versus getting pretty darn close to that. So I think that's where I would say 90% is about accurate of what I would do too. It sounds like you're higher than 90%. Yeah, I mean, to me, the technique to me, I think for me personally the safest technique is to get on the vessels and stay on the vessels and as opposed to getting close to the vessels because then you don't know where you are. So I think we can talk about this in a minute is the The difference between what a surgeon says they did in the operating room and and what the postoperative imaging says they did in the operating room, and those are not necessarily the same. In fact, we've studied that twice and found that they're very different. The first time we looked at it was when we were doing the pilot study for the tandem transplant and we Had compared the surgeon's op note for their degree of resection, and the cut points for that were less than 50%, 50 to 90%, or greater than 90%. And then we had the initial postoperative imaging study scored by the radiologist for the same, uh, for the same evaluation, those same cut points, and found that the surgeon overestimated their assessment of how much they resected. 2/3 of the time, so there was only a 66% concordance rate between what the surgeon said and what the what the imaging said. Now, interestingly, we repeated that study with the recent high risk children's oncology group. We went to all of the. Images are archived at the imaging Review Center, and we went with two surgeons and two radiologists, reviewed the radiology post-op radiology studies and reviewed the op notes, and the results were the same. There was only a 66% concordance rate, which statistically, by people who know a lot more about statistics than I do, suggests that there's no correlation. But it was exactly the opposite, that the surgeons uh uh overestimated the amount that they were sick. No, I'm sorry, the surgeons underestimated the amount that they resected and the radiology overcalled it. But basically I think what that says is what the statistics say, which is there is no correlation. So we talk about all these things, but the reality is we don't have a very good definition of what is a greater than 90% resection. So the other, the other question 72% of the audience, uh, would do a greater than 90% of. Great. OK. Um. Another question that frequently comes up is your oncologist comes to you after 4 or 5 cycles of chemotherapy and says this is smaller, um, but it's still surrounding encasing the vessels. Should we give more chemotherapy or will you take him to surgery now? So, who would advocate for additional rounds of chemotherapy? I go by what's happened from the cycle before is there's been a continued reduction. If it seems to, that there's no more reduction in their imaging, then I would consider surgical therapy. Mark, I'd just take them. Just take them. Has the patient had any regional local radiation? No radiation. I, I still think that's part of the protocol. Typically in the current protocols, radiation is given, given post-surgery, post-surgical control, and then the field is uh is radiated. Or to do more chemo or make it smaller or to try to take it out now. Take it out now. Agreed. They've had in this scenario 44 or 5 rounds, right after the 4th or 5th round, if it was if it was really shrinking, I would give more to shrink, but that's a rarity, I think most of the time it's done by then, and then I would just take them to the operator. I take him to the OR, try to get it out. And take them to the OR and, and that's our approach as well. And, and I think the only data we have to support that is um some data from Memorial Sloan Kettering that suggests that the biggest volume response in of the tumor is with the first two cycles of chemotherapy. And then after that, you really get very little response. The concern is that the more chemotherapy you give or other agents, and now things like MIBG, which is local radiation, um. Uh, that you actually make the tumor more fibrotic, and it makes that technique of getting down on the vessels and splitting it off much more difficult. And so you can actually make, I think, my personal opinion, and that's opinion not supported by data, I'll freely admit, uh, is that the more chemotherapy, the more treatment you give, the harder it gets. And we've actually argued. Um, in the children's oncology group to move the surgery up, uh, further. So after 4 or even 3 cycles of chemotherapy, as opposed to moving it back further with the hope that you're somehow going to make that an easier operation. All right, um. So Data suggests that aggressive surgery, and that's defined as a greater than 90% resection, is the next poll question up here, is that results in improved overall survival, reduced overall survival through complications, improved local recurrence-free survival, increased cumulative incidence of local recurrence or progression of metastatic disease. So the issue here really is. There are two questions. First, technically, which we've discussed a little bit, can you do it? And then obviously the bigger question is, does it help? And I think that this is where we have data that's conflicting and it's data that is critical because this is what drives the decision as to whether you Should put the patient at risk by doing a very aggressive operation. Are we still on a stage 3 patient, or are we a stage 4? Oh, thank you for bringing that up because I do want to get to that, um, and perhaps after we discuss that, I do want to discuss what people would do in the face of metastasis. So this is a stage 3, stage 3 patient. I think there's pretty good evidence that it does improve survival in stage 3 patients. I, I don't think there's a lot of data that would give a lot of support for stage 4, but for stage 3, I think, uh, there was one of the studies, uh, before the merger, years ago, before the COG merger that Jerry clearly showed that stage 3 patients benefited by total resection. Which to me makes sense, biologically makes sense. Unfortunately, the vast majority of these patients present with stage 4 disease. So to your question, uh, would you do an aggressive operation on a patient with metastatic disease, or under what circumstances would you do an aggressive operation on a patient with metastatic disease? Can you tell us what the mortality is from that operation? The data now with at COG in terms of Death on the table, bleeding to death. The mortality, a surgical mortality. Sure, I can tell you the complication rate in all of, in most of the studies is very consistent. It's about 30% complications, morbidity. The mortality is very, very low, less than 1%. So how do people feel about metastatic disease? Aggressive local control or not? Depends, it depends on what the local disease looks like. Well, what if it looks like this, you know, that it's, uh, so for the same patient, you would be less aggressive. Same patient, I might be a little less aggressive. I would like to, well, I, I think I would like to see how it responded to the chemotherapy if it shrunk the tumor and, uh, the chemotherapy cleared the bones. I would be more aggressive. If it had no effect on the bony disease, they still had high VMA levels, had minimal shrinkage of the tumor, I wouldn't be. You know, this is a question that's been asked for 30 years plus, and you'll find people on both sides of the coin about the approach to this, and, and they're like our personal study from Riley showed, uh, the only survivors with stage 4 disease were the ones that had primary tumor resection. The study from Sloan Kettering suggests they do better as, as well. Kylie's study said there's no difference. The European studies show there's no difference, and as far as I know, the most recent COG study shows there's probably no difference. So we'll get to that in just a minute because I'm going to show you the data, uh, from those studies. I, I don't know what the more recent therapy is, but if you look at the treatment. Of this high risk patient. Where they eventually get 9 different drugs, they get bone marrow transplantation. Some of them got total body radiation. The morbidity of the medical treatment for these patients is outrageous. Yeah, there's no question that the philosophy for these patients has been dose intensification to the point of doing tandem, not just one peripheral blood stem cell transplant, but two, so that as soon as they recover from the first one, you hammer them again and then transplant them again, and then ongoing therapy after that with immunotherapy and Retin-A. So, right, very, very aggressive therapy, but I think it's not uncommon for us to be in a position of being. Pressured by our oncologists to operate on the primary tumor. Our personal or my personal approach has been that if the metastatic disease has responded, and it may or may not have completely cleared, but at least if it's responding, then we would probably go ahead. I agree and it has to do with your point about what's the mortality associated with the operation. It's, but it's not trivial, 30% morbidity, and it's not trivial morbidity, um, for these cases. You're talking about a group of kids that at one point in time had a 10% survival. With all the intensification, it's gone up to 30 to 40% survival and with transplantation plus immunotherapy plus differentiating agents, the Georgia study showed a 46% survival, but like. The deaths were not due to cancer in many instances, it was due to the intensified treatment, yeah. So, um, let's just look, uh, quickly at the data and, and there are 3 studies that have, uh, not even been published, all of them yet. In fact, only 1 of them has been published. Uh, the other 2 studies were reported at the ANR meeting, uh, in Germany, but the German study has been published. It was published about a year ago. There were 278 patients with stage 4 high-risk neuroblastoma. Uh, they looked at the best resection obtained. Uh, 50, almost half the patients, they were able to achieve a complete resection and in another quarter of the patients able to achieve a greater than 90% resection. So, uh, 75% of the patients, technically you could achieve a greater than 90% resection. The overall survival, event-free survival 33%, the overall survival 45%, and the local progression-free survival of 58%. And that's all very consistent with all of the other studies from the US and other places which just suggests that the cohort study cohort is equivalent. These are the survival curves based on the completeness of resection, and it's a little hard to see because they're small, but the bottom line is there is no difference. There's no difference in overall survival. There's no difference in event-free survival, and there was no difference in local progression-free survival. So the conclusions from that German study, which was just published in January, I believe, is were that aggressive surgery is not justified, that limited operations decrease the chance for complications, and there's limited impact, if any, on the patient's outcome. And so you should not be doing these aggressive procedures. In contrast to that. At the ANR meeting in Germany in the spring, the, a large cohort of patients from the European study from Sien was reported. Um, I believe there were 1300, 1,324 patients. Um, and again, they used. Similar, not exactly the same, but similar cut points where a complete excision was greater than 95% and again 75%, almost exactly the same number, they were able to achieve a 76, 95% resection. So technically again suggests that about three quarters of the patients you can get to a complete resection if you define that as greater than 90 or 95%, and I would argue you can't tell the difference between a 90% and 95%. Um, their mortality, uh, to your, uh, question, Arnie, 0.5%, uh, mortality. Uh, morbidity was 10%, but if you look at lower, uh, lesser complications, it's up in the same 30% range. Their outcomes, however, showed that there was a significant improvement in event-free survival. And a significant improvement in overall survival, and this is the first study that's ever showed a significant improvement in overall survival. So this is, and it's a very large data set with 1300 patients. Um, so this is very important to support the aggressive approach that everybody in this room has suggested that they would, uh, that they would pursue. There actually now is some data to support that. Now that was more than just stage 4 though, right? 23, and 4 high risk. They're, they're high risk, so correct. Um, but it wasn't, it wasn't all patients with metastatic disease. They are comparable patients. I think they included 3s and 4s, 32 3s and 4s, um, correct, correct. So, so these patients are high risk patients in terms of their biology. Um, Uh, and then finally. I'm sorry, so their conclusions again, you should be aggressive that a greater than 95% resection results in an improvement in event-free survival. So you know, Dan, none of these studies that talks about what Doctor Grossfeld was talking about where you see how they, you know, what their response was to chemotherapy. Before you get there. I love it. Great point. And we're currently doing that study right now to see, to try to correlate the response of chemotherapy to the ability to achieve a surgical, complete surgical resection and what their outcome is, and that may help. That's a it's a very frequent. Criticism is that there's different biology and that you can't get a, the, the patients who don't do well are the ones who you can't get a resection on, and it's, it selects for the group. And so we're actually looking at that right now, um, to try and correlate the radiographic response with the surgical response with the outcomes. It's hard to do, obviously, in a single center because there are limited numbers of patients. So the final study then is just our results from the uh most recently completed high-risk study, which is the COG 3973. Uh, these are the uh survival curves and what it showed was a significant improvement in uh local relapse. So, uh, improved local relapse-free survival, which is the bottom curve on the left there, and an improvement in event-free survival, which is the curve on the right, statistically significant improvement in event-free survival. We were not able to demonstrate an improvement in overall survival. This is about 230 patients compared to the European study that had 1300 patients, and, and that may, it may be that the improvement is small enough that it's being, uh, it's a type 2 error and that we just don't have enough patients to show that. So I think there is some data to support now an aggressive approach surgically, which many people have advocated, especially in this country for a long time. And you gotta, you gotta put into the scenario too that if you're going to do these aggressive resections, for instance, the Kylie approach to going into the adventitia, this is not a, for a, uh, you know, an occasional pediatric oncological surgeon to do, and that will have more of a, uh, an impact on the results than probably the biology of the tumor. Uh, and, you know, if somebody's doing one of these every year or one of these every other year, that's not appropriate. It gets the, the whole business of what do you, what cases do you refer in general in pediatric surgery, but this is one that I don't think, I mean, people like Mike Lauaglia do this all the time. Ed Kiley did it all the time, and, and they didn't get into trouble. I see when the occasional pediatric surgeon is gonna do this, they're gonna get into trouble, and they're gonna get, get into the aorta, the vena cava, when they do that dissection. I've seen Ed do it. That's not an easy operation. No, I agree with you. I, I, it's, uh, brings up the, brings up a very complicated politically hot topic that Samir or Abdullah actually raised earlier about the referring fetal patients. If you're not comfortable taking care of them, you should send them to somebody that is. And so, uh, in, in European studies, that one of the issues has been that they're. Those procedures are done in more than 200 hospitals, so, uh, even with that process in place, they still were able to demonstrate improvements in survival. But I think your point is a good one. Dan, about 15 years ago, there was some stuff that came out of the literature that if a nephrectomy was done in some of these patients, that they actually did better because you got better local control, presumably from a more complete resection. But I have certainly avoided any kind of uh removing any, anything more than the tumor. What's been your experience, and do you have any thoughts on that? Yeah, and so I think some of the older data data actually shows the opposite, that if you take out the kidney, the survival is worse, and so the philosophy and the approach is always if you can preserve the kidney, and that means you have to take forever dissecting out the. Vessels and such that the outcomes are better and that probably relates back to the comments Dr. Grossfeld made about the intensification of therapy that if you have only one kidney, you cannot get as much chemotherapy and that probably impacts your overall survival. So certainly renal preservation should be the the approach. OK, there was a question about recurrent disease. you go after that. Yeah, it's a, it's another one of those, um, as my father used to say, if you can't be informed, be opinionated, and I think, you know, we, uh, we, we tend to go after recurrent disease as long as it's not progressive metastatic disease, uh, we would, uh, we would be aggressive in, um, in addressing local recurrence for local control, but certainly those patients have a much worse prognosis. But now that we're getting other therapies like MIBG targeted MIBG therapy, uh, there may be ways to control those sorts of, um, to control, uh, more distant disease that would justify taking out bulk disease, uh, surgically. And I think that's the argument, the other argument for getting to a 95% resection is that we are getting some new therapies like immunotherapy that are effective in the setting of minimal residual disease. And if you can get to the point where the patient has minimal residual disease, however you define that, then that may improve the the impact of the medical therapy on the metastatic disease.