Wednesday, July 1, 2009

Another Perspective on the Induction Decision

As parents of children with neuroblastoma, we often make treatment decisions based primarily to two factors. The first is based on response. What treatment has the highest response rate? What treatment is going to create the biggest change? The second thing we consider is toxicity. What side effects come with this treatment? What is the impact on quality of life? Will something bad happen? We then take these two factors, mush them up in our brains, and spit out the answer for what treatment plan we follow.

Done. Easy answer.

Hold on. Unfortunately, this formula misses some very important considerations and often can lead you astray. The fact is that we don't live in a world which only has two factors - response and toxicity. Every decision we make has implications which will impact future decisions. In this way each decision also caries a significant risk factor. There is risk that a particular choice will make you ineligible for something later on down the road. There is risk that your child may not respond or the risk that something will happen that will preclude you from getting treatment. As I will try to demonstrate today, these are all extremely important factors that should weigh heavily on any decision. In today's high risk neuroblastoma treatment reality these may even be the most important factors to consider.

This is where my difference of opinion lies.

One of the appealing aspects of treatment at Sloan Kettering is the promise of no transplant. According to them, in their experience, they do not believe a transplant is necessary when antibodies (3F8) are used for consolidation of minimal residual disease. I should point out that this is in direct contradiction to three large randomized phase 3 trials which showed that transplant increased event free survival by 11% or more (these trials did not include the use of antibody, however.) Regardless, when analyzing the toxicities of transplant it is easy to be swayed by the allure of not having to have a transplant and the hope of achieving the same desired result. It is very appealing. People evaluate the response - children appear to achieve remission in similar numbers - and then they evaluate the toxicity - it isn't a transplant. The problem with this type of thinking is that it misses some extremely important factors. First and foremost, it misses the point that you are giving up on the proven standard. This is not additive treatment, this is "instead of" treatment. By not transplanting, you are risking the loss of an increase in survival of over 10%. It may very well turn out that the doctors at Sloan may be right. Someday, it may be proven that a transplant is not necessary given the medical technology at that time. But, in the meantime, you are very definitely adding more risk to your child's chance of success by not transplanting. You are gambling a 10 to 15 percent increase in survival in the hope that this other treatment (antibodies) will do the same job - a job that they are yet to be proven to accomplish. I think every one would agree that, in this case, if you looked at it from the perspective of this type of risk (the risk of decreasing survival), the best option would be to do both.

Another risk that many people do not think to consider is the risk of not being able to receive the treatment. This is one of the saddest realities of all. What if you decided to go to Sloan Kettering? What if you decide to reduce your risk of toxicity from transplant and forgo it? What if you decide to use 3F8 for consolidation instead?

What if you HAMA'd in the first or second round precluding further treatment?

This risk is significant. It happens. There are kids sitting in this scenario at this very moment - kids that could have been transplanted and received antibody. But, the question remains. You gave up transplant in the hopes of reducing toxicity in favor of a relatively unproven treatment (for this purpose) and now, because of a fluke, because of an immune reaction, you are no longer eligible to receive that treatment either. Or, you are no longer able to receive that treatment again with out some significantly high doses of chemotherapy - high doses of chemotherapy which offer significant toxicity but still do not provide you the benefit of a transplant or any guarantee that you will be able to get enough antibody to get the job done. In this scenario, the nightmare, you have actually increased your risk on at least two fronts. Your decision cost you the benefit of a transplant (11%+) and the benefit of antibody (20%). By choosing this route you have effectively reduced your chances of survival by over 30%. Could you go back and do a transplant? Probably. But, would you become eligible for the ch14.18 antibody? Not today.

That is a big gamble - an especially big gamble for something that is yet to be proven.

The third risk is the risk of treatment failure. I know this is something that no one wants to consider but, it too does happen. In fact, I have seen some articles quote numbers as high as 20% (or higher) of patients fall into this category. In this scenario, the standard therapy has failed in induction. You have done your due diligence yet, even given the best medical knowledge we have, your child has failed induction. What are the risks here? What impact did your decision of which path to take have in this scenario? I think the risk here is in eligibility. You see, if you fall into this category of patients the most important thing you can have is options. By participating in a standard induction you are naturally eligible for several options that you might not be otherwise. An example of this would be an MIBG/transplant regimen. This type of transplant has been extremely effective for a subset of these individuals. In fact, for some, this was the ticket that got them back onto the road to survival. I am not advertising this trial but simply pointing out that this is a treatment that is available and effective for a certain subset of the non responding population that may not be available to them if you decided on a different path from the beginning. It is just one example of risk in this group of patients.

Finally, before I run out of internet, I would be remiss if I did not address the most obvious but less publicized risk. By choosing not to participate in a COG trial, at this point in time, you run the risk of not being able to receive the ch14.18 antibody. This is the one antibody that has been proven in a randomized phase 3 trial to increase survival by an additional 20%. One could easily argue that choosing not to utilize ch14.18 carries inherent risk.

Now, please, don't send me email telling me that 3F8 can do everything that ch14.18 can do. Trust me, I know what it can do. The point is that by choosing 3F8 over ch14.18 you are taking on more risk. At this point in time ch14.18 is a proven commodity. We don't know whether 3F8 works better, the same, or worse. Furthermore, with 3F8, we also have the additive risk of an early HAMA - a risk that is greatly minimized by the ch14.18 antibody.

You see, today is not about response or toxicity. My arguments have absolutely nothing to do with which treatment is better. That is another discussion entirely. This entry is about reducing risk and increasing options.

Risk is the third ingredient of the treatment decision that we often forget to consider fully. This is unfortunate when, as I have demonstrated today, it just might be the most important component.

Let the email fly!

It is all part of the purpose equation.

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