Sense or Science?

There has been a lot of talk over the last couple of years about personalized medicine. These talks have even trickled over into the world of neuroblastoma. On the surface, it seems intuitive. Analyze the kiddo's neuroblastoma, see what drugs would work in the lab to kill that child's disease, and then give the child that drug. It seems simple enough. Right?

In a perfect world, yes. But, in reality, this is much more difficult and my fear is that we are not quite there yet. However, does this mean we should not be pursuing personalized strategies in relapsed neuroblastoma?

There are many examples in neuroblastoma where we could use these strategies. Accutane and it's use is a perfect example. According to a phase III study, the gold standard of clinical research, it has been shown that Accutane increases survival when given during the maintenance phase of treatment. Clearly it does not work for everyone. If it did, there would be many more survivors and fewer relapses. None the less, it still does increase your overall chance of survival. How, though, do you ensure that it is working for your child and what should we be doing to ensure that it is?

This is where personalized medicine comes in. From animal studies we know that we have to get a certain sustained concentration of Accutane in the animal before the drug can go about its business of killing neuroblastoma. Therefore we have assumed that for people to benefit from it we must also ensure that they reach this threshold as well. From pharmacokinetic studies we also know that the drug is absorbed into kiddos bodies at all different kinds of levels. Some kids get really good levels of Accutane - others not so much. It is extremely variable. The reason(s) for this disparity are relatively unknown although there are all kinds of theories. It could be the food that they take with the drug. It could be genetics. It could be a myriad of factors.

Regardless, by design the amount of drug that is given to these kiddos is essentially the amount that appeared to allow as many as kids as possible the ability to achieve the necessary drug level to kill neuroblastoma without causing unreasonable side effects. It seems a reasonable method of establishing a dose, does it not? - Trying to help the most kids you possibly can without causing needless side effects - what a nice concept.

It is a reasonable method. Unless, of course, you are one of the children that is not benefiting from the drug because you aren't achieving the drug levels necessary for activity yet you are still receiving all of the "benefits" of the side effects.

It seems this is a perfect opportunity for personalized medicine. What if there was a test that you could take during your treatment with Accutane that could tell you whether or not you were receiving enough of the drug to achieve the necessary levels for activity? If that existed, you could adjust your the amount of drug or your child's diet to increase absorption. For those that are achieving high levels of activity you could perhaps cut back on the dose to spare a child from side effects.

That is personalized medicine.

However, is it that simple?

It turns out that you can get such a test completed. Obviously, if they were able to do the PK studies to see that drug levels were different they could make this into a test. So, yes, even today, you could find a way to get this test done on your child.

However, there is a rub. While we do know that it takes certain levels in mice to see activity we really don't have any proof in humans. We are assuming that it translates from the animal model to our kiddos. The fact is that, at this point, we really don't have any proven correlation between more drug and more activity in humans. It is what we believe. It is the direction that all of the evidence points but, the fact of the matter is that, a study has never been completed that proves this (although some are in progress.) So, while it appears that we know the answer, we may very well not. In fact, stranger things have happened and in reality there are many similar examples in cancer treatment where less could, in fact, be more.

So, even with Accutane there are tests that we can use to help personalize medicine. The problem however is that we don't truly know what to do with that information. We often have the capability to test a tumor or a patient to identify certain characteristics of their disease. We even often know of drugs which have been shown in preclinical models (rats, mice and Petri dishes) to kill disease which has those characteristics. Unfortunately, we just don't have any proof that it actually will work in our kids or work better than the "standard" of care. I wish I could say that preclinical tests often predicted the outcome of a particular treatment but unfortunately history shows the opposite. There are mountains of therapies sitting in the wastebasket because the reality did not live up to the preclinical proof.

Do we go with what has been proven or what is likely? In relapse, is it even a choice when there is nothing that is seemingly proven?

This is the type of problem which impacts much of personalized medicine in neuroblastoma treatment. This is why I say, at this point, it is more sense than science. There are no absolutes. There is nothing proven and until it is it will not make it into mainstream neuroblastoma treatment.

Now, the last thing I want to come off is anti-personalized medicine. I am very much the opposite. In fact, if Sydney were to relapse today you can bet that I would very definitely be informing my decisions based on characteristics of Sydney's tumor. I would be checking her disease against drug panels. If she was going to face Accutane again you can bet that I would probably be checking her drug levels. Would these findings dictate our treatment? Absolutely not, but you can bet that they would influence it.

It isn't science. It is sense. But that doesn't mean it is not helpful.

And the one thing I know for sure is that we need more science and more proof so that we can make a personalized medicine, the science, a reality.

Just so you know, there are a few ongoing studies looking into personalized medicine. All are viewed with a grain of salt as they should be. But, that does not mean that they should not be viewed. It is the interpretation that needs a grain of salt.

In this case information is purpose too.