Neuroblastoma: Update Course 2014

I want to turn over session two to our course director Dr. Dan Von Olman. Thanks Todd and welcome back everybody. Uh we're going to start we we have some very different topics uh this time around. Uh uh we're going to start off with a couple of uh tumors 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 uh reducing therapy uh all the way down to Jed Nocturn'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 uh persists is what to do with the high-risk patients. And uh those patients uh presents 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 advance the slide. Okay, so I just want to uh as has been the format here, start with a very straightforward case uh presentation. 18-month-old presents with an abdominal mass noted on 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, is mildly anemic. uh the urine catacolamines are elevated. And uh next slide mark. I can try this. Yeah, work. Um you get a physical exam that shows this uh abdomen on physical exam and a CT scan that uh looks like the panels on the on the right there. So the the question we want to address here is from a surgical standpoint is how important is the completeness of resection of the primary tumor uh to control both local recurrence as well as uh patient outcome. And this is something that has been argued back and forth. Uh there is some relatively new data that's just come out uh within the past year actually supporting both sides of this argument. And so I'll be interested to hear uh 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 uh do a biopsy only or minimal resection or we 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. Kylie uh where you get down to the adventia and do a complete resection of these large retroperitoneal masses completely um uh removing uh 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 polling the audience as to what we 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 at time of diagnosis or after chemo? Great question and uh that actually brings on another question uh but let's say gets the standard five cycles of chemotherapy and has a residual tumor that is decreased in size but continues to encase the uh retroperitoneal vasculature and the aorta, the vena cava. 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 three 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 a case with uh tumor limited to the abdomen without metastatic disease. Yeah, we would try to do a complete resection if possible. Agreed. Yeah. Would anybody not? Oh I want I want to particularly ask our uh Dan? Dan, uh we can't hear you, Dan. you must be muted. Uh we would try and achieve a we would do a 90% resection, not not sacrifice anything important. Others I can. Samir? Samir? Yeah, I I'd try and do a 90% resection as well. I agree with that. All right, uh Beno? I don't know if Beno's on the phone. It looks like uh we lost our European colleagues. Um So a quick question uh Dan, what would you do in terms of the technique? Would you use Ed Kylie's technique getting into the subadvential area of the vessels or would you do go short of that? I I would use that technique and I think that 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 subadvential plane peeling the tumor off of the vessels as opposed to working your way through the tumor and finding yourself in the vessels. I would agree with that. Yeah. So I think, you know, the the two ends you gave were debulk versus uh. Yeah, it'll come back. Um Mark they can still hear us, right? Okay. So um I I would say that 90% resection. 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. Sounds like you're 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 uh I think and we can talk about this in a minute is the um the difference between what a surgeon says they did in the operating room and that and what the post-operative 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 the they're uh very different. The first time we looked at it was when we were doing the uh pilot study for the tandem transplant and we had uh compared the surgeons op note for their degree of resection and the the cut points for that were less than 50%, 50 to 90% or greater than 90%. And then we had the initial post-operative 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 uh two-thirds of the time. So there was only a 66% concordance rate um between what the surgeon said and what the and 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 uh imaging review center and we went with two surgeons and two radiologists reviewed the radiolo post-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 suggest that there's no correlation. But it was exactly the opposite that the surgeons uh uh overestimated the amount that they resect. No I'm sorry, the surgeons underestimated the amount that they resect and the 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 way 72% of the audience uh would do a greater than 90% resection. Great. Okay. Um Another question that frequently comes up is your oncologist comes to you after four or five cycles of chemotherapy and says this is smaller um but it's still surroun encasing the vessels. Should we give more chemotherapy or will you take them to surgery now? So who would advocate for additional rounds of chemotherapy? I go by let's happen from the cycle before is there's going to be 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. All right. I still think that's part of the protocol. Typically in the current protocols radiation is giving given post surgery. Post surgical control and then the field is is radiated. Would you do more chemo or make it smaller or try to take it out now? Take it out now. Agreed. They've had in the scenario for four cycles. Four four or five rounds. Right. After the fourth or fifth round if it was if it was really shrinking I would give more to shrink it, but that's a rarity I think. Most of the time it's done by then and then I would just take him to the operating. I'd take him to the OR try to get it out. Right. Same take him 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 that 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 four or even three 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% uh resection. That's 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 uh uh 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 three patient or are we a stage four patient? Oh thank you for bringing that up because I do want to get to that. Um and perhaps after we discussed that, I do want to discuss what people would do in the face of metastasis. So this is a stage three. Stage three patient. I think there's pretty good evidence that it does improve survival in stage three patients. I I don't think there's a lot of data that would give a lot of support for stage four, but for stage three I think uh there's one of the studies uh before the merger years ago before the CG merged. clearly showed that stage three patients benefited by total resection. Which to me makes sense, biologically makes sense. Right. Unfortunately the vast majority of these patients present with stage four 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 uh in terms of death on the table, bleeding to death, surgical mortality. Sure the 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? 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 see. 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 bone, disease, 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 there like our personal study from Riley showed uh the only survivors with stage four disease were the ones that had primary tumor resection. The study from Sloan Kettering suggests they do better as well. Right. 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 reality is. But if you look at the treatment of this high-risk patient where they eventually get nine 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 retinoid. So right, very, very aggressive therapy. But I think there it's not uncommon for us to be in a position of being pressured by our oncologist 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 and it has to do with your point about what's the mortality associated with the operation and it it's but it's not trivial, a 30% morbidity and it's not trivial morbidity. 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. So um let's just look uh quickly at the data and and there are three studies that have uh not even been published all of them yet. In fact only one of them has been published. Uh the other two studies were reported at the INR meeting uh in Germany. But the German study has been published. It was published about a year ago. There were 278 patients with stage four 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 of 33%, the overall survival 45% and the uh 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 suggest that the cohort study cohort is equivalent. These are the the survival curves um based on the completeness of resection and uh it's a little hard to see because they're small but the bottom line is there is no difference. There is 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 decreased the chance uh for complications and there's limited impact if any on the patient's outcome and so you should not be doing these aggressive uh procedures. In contrast to that at the uh INR uh meeting uh in Germany in the spring, the a large cohort cohort of patients from the European study from Siapen was reported. Um I believe there were 1300 yeah 1324 patients. Um and again they used similar, not exactly the same but similar um 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 um a 95% resection. So technically again suggest that about three quarters of the patient 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 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 uh event free survival and a significant improvement in overall survival and this is the first study that's ever show to 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 uh 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 four though, right? 2, 3, and 4 high risk. They're high risk. So correct. Um It wasn't it wasn't all patients with metastatic. Right. They are comparable patients. I think they included threes and fours. Two is three's and four's. Two three's and four's. Yes. Um. Correct, correct. So so these patients are high risk patients in terms of their biology. Um. Uh and then finally I'm sorry, there so their conclusions again, you should be aggressive uh that a greater than 95% uh resection results in an improvement in uh event free survival. You know Dan, none of these studies uh talks about what Dr. 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 going to it's a a very frequent criticism is that there's different biology and that you can't get out 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 they're limited numbers of images. So the final study then is just our results from the uh most recently completed high risk study which is the C3973. 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 uh compared to the European study that had uh 1300 patients and and that may it may be that the improvement is small enough that it's being uh it it's uh a type two error and that we just don't have enough patients to show them. 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. Dan, you got to you got to put into the scenario too that if you're going to do these aggressive resections, for instance the Kylie approach to going under into the adventia. This is not a for a uh you know, an occasional pediatric oncological surgeon to do. And that will have more of a fact 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 what cases you refer in general in pediatric surgery, but this is one that I don't think. I mean people like Michael do this all the time. Ed Kylie did it all the time and and they didn't get into trouble. I see when the occasional pediatric surgeon is going to do this, they're going to get into trouble. And they're going to 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 issue. Very politically uh hot topic that Samir or um 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 the 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 uh improvements in 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 re removing any anything more than the tumor. Uh what's been your experience and do you have any thoughts on that? Yeah, and so I I think the the some of the older data data actually shows the opposite that if you take out the kidney, the survival is is worse. And and so the the philosophy and the approach is always if you can preserve the kidney and that means you have to take forever dissecting out the hiler vessels and such um 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 uh the approach. Okay. There was a question about recurrent disease. We can 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 and 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 uh 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 uh impact of the medical therapy on the metastatic disease.