Monday, October 18, 2010

Toxic thoughts on Anti-GD-2 antibody therapy

There were many interesting little nuggets of information that could be taken away from the New England Journal of Medicine article "Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma." Some of which was surprising (at least to me), but all of it was important for a child with neuroblastoma. From side effects and prognostic factors to survival curves there was something for everyone. Yes, there was even mention of a 20% increase in survival due to this regimen. But, there was also a treasure trove of other interesting factoids.

I think the things that caught my eye first were the side effects mentioned in the article abstract.
In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively.
Now, before I dig into this I have to disclose that I have a bias when it comes to antibody therapy. After watching my daughter go through 18 rounds of anti-GD2 antibody therapy, watching 100s of other children go through it and then having 7 years to reflect upon it, I have an opinion which is steeped in experience and tempered by time. So, before I share what I found interesting in this article you should know this, I believe in antibody therapy and if I had to make the decision to put Sydney through it all again, I would do it in a heart beat - and frankly so would she.

So, with that being said, let's begin.

I was absolutely amazed that only 52% of patients experienced grade 3, 4, or 5 pain. What you cannot read in the abstract is that they also found that grade 3, 4 or 5 pain was only experienced during 25% of 598 cycles of immunotherapy. Shocking! In my experience pain was almost universal and I would not enter this treatment with an expectation of anything less. Yes, I know what this phase 3 study results say. But still, I can also tell you that I have only seen intense pain not be a factor in one lone child receiving the ch14.18, as given in this study, and in children receiving 3F8 that had experienced a HAMA. So, if you have a child that is getting ready to enter antibody therapy, do not take my words lightly. Take my word for it. Your child will experience pain. It will be horrible. In fact, the first day may well be the worst day of your life. It is awful. Watching your child endure it is the stuff nightmares are made of.

But still, do it.

Now, here is the good news (and I mean this in the most heartfelt way possible coming from a dad that has been there), the child probably won't remember a darn thing unless they are older than 7 or 8. Yes, you child will end up being so drugged up they won't have any memory of the pain or the treatment. Unfortunately, for you, that is not the case. You get to live with the memories of the pain and agony for the rest of your life. But, I can also tell you this, the pain (your pain) fades over time. (Their pain ends with the infusion) In fact, you have probably been saying the whole time, I wish I could bear all of this treatment for my child. This is your opportunity. While you still can't do the treatment it is you that will have to carry the weight of the memory of the treatment for your child.

Sydney had antibody therapy from the age of 4 through age 6. She has no recollection of the pain and, in fact, she only remembers her time at Times Square, a few of her favorite nurses and the taste of the hard boiled egg that she would cherish every morning. The pain and the discomfort have all been lost and replaced by happier times. I should also point out that this seems fairly consistent with nearly everyone I have met.

The bottom-line is that you should prepare yourself for your child to endure pain. Be prepared to advocate for your child and to be on top of the pain meds. With the right mix of timing and morphine you can make this trip a far more pleasant one for your child. Again, the great news is that this treatment could likely prevent relapse and save your child's life and your child will have little or no memory of it.

The other side effect that shocked me a bit was that of capillary leak syndrome. A quarter of patients seems about right. I had always attributed it to the use of the world's nastiest drug, IL-2 (my non-medically trained opinion). However, while it occurred more frequently during cycles 2 and 4, which involved IL-2, with incidences of 11% and 13%, respectively, it also occurred in cycles 1, 3, and 5 during courses involving GM-CSF (incidences of 3 to 7%).

This trend was found with hypersensitivity reactions as well. Grade 3 or 4 hypersensitivity reactions were reported in 25% of patients, during 15% of immunotherapy cycles. Hypersensitivity reactions were more frequent during the two cycles involving interleukin-2, with incidences of 26% and 25%, as compared with 5 to 12% during the three cycles involving GM-CSF (P = 0.001). Such reactions may be attributable to symptoms and signs that reflect both toxic effects of interleukin-2 and antibody-related hypersensitivity.

Finally, the side effect of fever was the other thing that shocked me. Only 39% of patients experienced fever. Again, my experience is that fever is universal in rounds that include IL-2. In fact, I have never heard of a child not experiencing high fevers with the use of IL-2. I, honestly thought 103 and 104 degree fevers were universal and I seriously draw that statistic into question. In short, I would not be surprised when I saw my child experience a high fever during IL-2 treatment.

Several times throughout the article they mention how this regimen was associated with important treatment-related clinical toxic effects. As much as I felt that the incidence of side effects was far less than I had perceived I was surprised by how much worse the article made the side effects seem. Yes, there was pain, some capillary leak syndrome and hypersensitivity reactions. However, compared to the toxicity of chemotherapy or radiation it was a walk in the park. There is no hearing loss, no cardiotoxicity, no mountains of lifelong toxicities to look forward to. In comparison to everything our children had faced up to this point it seemed almost not even worth mentioning. (although I know they had to).

In short, I was surprised that there were not more toxic effects than there were. I expected them to impact far more patients than they apparently did. However, I was also surprised by the discussion of the toxicities. To me, the article made them sound much worse than they really were. Regardless, I think the article continues to make an incredible argument for the importance of antibody therapy.

Nobody ever said that raising the survival curve by 20% would be easy, just be glad that, for your child, it will not be memorable.

More purpose to come.

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