Thursday, July 24, 2008

The CNCF Neuroblastoma Conference - a review

Good morning! Well I am happy to report that we have officially turned the corner on Sydney's behaviour. It seems like we have officially established some boundaries and she understands what they are. Now, I can't guarantee that she will never act out again but I can tell you that she is aware of her behaviour. She knows what is unacceptable even when she is angry. Yesterday, aside from a few pouts that some things did not go her way, she was utterly perfect. 2 days down and only 19 more to go until we have established an official habit. We will watch closely. I am not saying that she is no longer a twerp, just a more balanced one.

Well, before it escapes my mind I really want to talk about the conference. I know there are parents out there that are really curious as to what was said. I think one of the most interesting discussions concerned transplant options. We had a panel consisting of Dr. Bolotin, Dr. Yanik, Dr. Yamashiro, and Dr. Cheung. Each were responsible for representing a certain opinion on transplant. We discussed the new Topotecan containing single autologous transplant regimen from City of Hope, MIBG/transplant Combinations, tandem transplants, allogenic transplants and Sloan's option of no transplant at all.

Over all ,I though the discussion was very good. As one should expect it became very clear that there is no answer right now. There just isn't. I am not being sneaky, biased, or opinionated. There is simply no clear answer.

There are some general rules, however.

Tomorrow, I will hit upon some of the general rules that I think we established. Today I will hit upon why there is no clear answer between one decision and another. People will always continue to compare statistics from one institution to another. This is only relevant if the statistics that you are comparing are actually the same. I can tell you from the basis of our discussions at the conference none were using the same measure. I will explain.

Dr. Bolotin showed a survival curve for their Topotecan containing transplant. Ironically, you could not see a curve because it was a straight line at 100% survival. That seems the obvious choice doesn't it? Hold on? Her curve only included 8 patients and it was only for a period of 333 days. That is not long. That means the eight patients they studied were all transplanted sometime in the last 333 days and they were all surviving so far. I don't mean to shock anyone but that isn't surprising. First off, this transplant regimen only includes responders to upfront therapy. I would fully expect the vast majority of them to be responding at this point regardless of the treatment. It shows that City of Hope is a good transplant center but beyond that it really does not answer many questions. We need to wait another 5 years to look back on the data and see what an actual curve looks like then. In this case we are looking for lower toxicities and hopefully no reduction in survival. It is interesting to note that Topotecan could actually increase the survival in this regimen due to a mechanism of action that was totally not expected or anticipated. You will need to watch the video to find out more.

Dr. Yanik showed several curves but I will start with MIBG. I don't remember the exact survival percentage but it was in the neighborhood of 25 to 35% over 3 years. Would you believe that this could possibly be the best option? You see his data was event free survival. Not overall survival. So, many kids may be surviving that are not in this curve because they are taken off the curve for many different reasons. They are taken off for "events," like severe toxicities, relapse, etc. The good news is that we know that the "survivors" are doing fairly well. The other incredibly important thing to note is that these statistics also include the hardest patients to cure. You see, when this data was collected you could not be on an MIBG/transplant trial without having failed induction chemotherapy. These kids are the worst of the bunch and the hardest to cure. The fact that so many of them survived so far out is incredible. This study was also hard to get a handle on as many patients were treated at different dosing levels. Although the number of patients was good (nearly 80 or 90 if I remember correctly) it clearly was not comparable to some of the other options.

Dr. Yamashiro presented some data on allogenic transplants. It was this section that I probably learned the most about from the entire conference. Essentially the idea from an allogenic transplant is to create a graft versus tumor (GVT) effect. In this case you not only receive the benefits from a typical transplant but many also benefit from the GVT effect. In this scenario the donor cells not only reseed the marrow but the also attack tumor. It is very interesting. The problem with allogenic transplants is that the are extremely dangerous and come at a cost. His review showed a morbidity rate of a little over 30%. This means over 30% did not survive the allogenic transplant. The survival rates were not bad but we have to be concerned about at what cost. In an effort to reduce the morbidity Dr. Yamashiro started doing autologous transplants followed by a mini allogenic transplant. It is the science and technique of how this is done that was such a learning experience for me. Regardless, the hope was that this method would reduce the toxicities associated with a complete allogenic transplant while still benefiting the patient with GVT. Based on the data it certainly looks like he is able to meet both of these objectives. It was hard to compare his survival statistics as well. The numbers weren't bad but his patient numbers were small. Also, I happen to know from reviewing this study at the ANR in 2006 that his patients were ultra high risk. It included many n-myc amplified kids. To me it looked like the group was one of the hardest to cure when looking at them at diagnosis. The point is that this group, too, was not really comparable to the other two.

Both Dr. Yamashiro and Dr. Yanik also gave a review of the rationale behind single and tandem transplants. A couple of things were clear from these presentations. In the COG hands, a transplant was clearly better than no transplant (although they never used antibody for consolidation). Another thing that occurred to me that there is hope that a tandem transplant will be better than a single. From what was presented, early clinical data seems to lean that way. Also it was interesting to note that the toxicities did not seem to be any worse. Strangely enough, in some studies they were even better. Regardless, this data was presented at 3 year Event Free Survival and since it is not comparable to the others I don't really see the pointed in repeating them here. They are well published in prominent journals.

Finally was MSKCC's option of using antibodies for consolidation instead of transplant. Dr. Cheung used an entirely different measure in an entirely different patient population than the other groups. At first his 3 year survival curve of approximately 77% looked great until you started to pick apart exactly what was being measured. This isn't to say the Dr. Cheung was intentionally deceiving anyone. He is not sneaky as far as I am concerned. In fact, he sought me out and we discussed statistics at length (about 30 minutes). He genuinely believes his measure is the most important measuring stick of success. I understand that. I don't necessarily agree but I genuinely see his point that "event free" survival curves are nebulous at best. Regardless, as much as I fought for a comparable answer we did not have one. The MSKCC survival statistic was only based on survival. It did not include "events" or "relapses". It was survival - period. The population included the best subset of stage 4 and nmyc amplified kids over the age of 18 months. These patients were also only ones that responded to upfront therapy. In essence they were the best patients that had a history of clearly responding. It simply isn't comparable to anything else that we have seen. I like Sloan. I like the people. But, this statistics gave us absolutely no indication of whether their therapy is better or worse than any other.

Put in it's simplest terms. After they finished their presentation I asked the question of which treatment strategy was best. I think it was clear to everyone that there is absolutely no answer. There just isn't.

Finally, not one of these studies was shown at 5 years (mainly because the data was not available because the studies are not old enough.) That is a far better time period for us as parents to make a decision. I think everyone agrees upon that. A lot more shakes out over that time period.

The trick becomes, how do we use this information. Well, the good news is that even though all of this is extremely tricky and murky we were able to get to the bottom of a few rules that were agreed upon by everyone. There are answers amongst all of this mess.

Everyone seemed to have purpose. They just couldn't agree on how that purpose should be measured.

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