Thursday, 19 May 2011

Clear. As. Mud ...

Here’s the thing. As a few of you will no doubt already be aware via twitter and facebook, Adam’s FDG-PET scan came back completely clear. No abnormal uptake of the radiotracer was detected anywhere. But what does that really mean? And how does it affect our thinking and plans going forward? The first thing to say is it didn’t entirely surprise me that the scan came back clear, I expected any uptake to be much less widespread and intense than what we see on mIBG scans. It’s definitely a positive result, the best we could have hoped for; but at the same time (unfortunately) it’s neither remarkable nor game-changing.

The scan that Adam has been having regularly for the past 22 months is called an mIBG scan (meta-iodobenzylguanidine). This substance is picked up by receptors on the surface of neuroblastoma cells. For scanning purposes it is radiolabelled i.e. has a radioactive tracer attached to it (usually radioiodine I-123) that can be detected by imaging equipment. It is probably the most specific, most accurate and most widely used of all diagnostic techniques for detecting neuroblastoma. Of course, like almost everything else it’s not infallible. Some children present with non-mIBG avid disease, or their neuroblastoma mutates to become such. It also does not give any information regarding how differentiated the cells are that take up the mIBG; immature, aggressive neuroblastomas, and mature, non-dividing ganglioneuromas, look the same under mIBG scanning. Finally, it cannot tell anything about the metabolic state of tumour cells; fast-growing, or indolent, they will appear identical.

The scan that Adam has on Monday was an FDG-PET scan (fluorine-fluorodeoxyglucose). FDG is a glucose-like compound to which a radioactive tracer (different to that used in mIBG scans) is attached. It’s readily taken up where high amounts of glucose are used – by organs such as the brain and kidneys, but also by tumour cells. Tumour cells metabolize glucose and therefore abnormal FDG uptake is found where there is active cancer.

Putting the two scans together, and considering what this means for Adam things hopefully start to become clearer. Adam still has a lot of disease, his spine, pelvis and femurs are riddled with abnormal cells, as evidenced by his mIBG scan. However, there is currentlylittle going on in those abnormal cells, as evidenced by his FDG-PET scan. The result of the FDG-PET scan is good, but mainly because it would have been bad if there had been significant uptake on it. A clear PET scan is not, and never will be, a substitute for a clear mIBG scan.

I said earlier that I wasn’t surprised by the latest scan results. Although I didn’t necessarily expect the scan to be completely clear, I didn’t expect there to be significant uptake (although it’s always impossible not to worry that something nasty is going to show up). My thinking was that Adam has had stable disease for the best part of twelve months now. If he’s got stable disease that means either treatment is holding it at bay, or the cancer itself hasn’t been doing a whole lot. Reflecting on what he’s had in the last year, and the fact that biologically he was diagnosed with the most aggressive form of neuroblastoma, I think that for some unknown reason his disease has, for now at least, just gone into hibernation. Maybe the MIBG therapy he had in October and January did something – Adam scan results are consistent with responses that have been seen in some other children. We can only speculate because this is the one and only PET scan Adam has had, so at what point his disease first became inactive will forever remain a mystery.

So Adam’s disease is inactive. I’d love to believe that it’s all matured, that the cells have divided as many times as they are going to divide, and that things are now just going to remain in this state. But truthfully, deep-down inside, I don’t believe that for one minute. Maybe one day, but not today.

Even if I did believe it consider this; the majority of children with neuroblastoma do achieve a first remission, their mIBG scans show no evidence of disease (NED). And yet of these children somewhere between 40% and 60% go on to relapse, the neuroblastoma comes back. Despite all the intense, destructive, super-toxic, treatments these children are given residual disease still remains at the end of it. Too small to be detected using current imaging techniques, even the most neuroblastoma specific, the mIBG scan. Yet eventually this residual disease grows and multiplies to become a full-blown, observable, relapse. If a child who is ‘in remission’ has minimal residual disease that can’t be seen, in my own mind I have already decided that Adam has other areas of disease, not showing on any of his scans, but which nonetheless are active and which will, given time, result in new tumours forming. So we have to think about this, as well as what does show up on the mIBG scan. It’s why we put him through high-dose and transplant despite having a positive mIBG scan. It’s why we are starting him on cis-retinoic acid, a super high-dose vitamin A derivative which has been shown to cause differentiation in neuroblastoma cells, turning them into mature cells that will no longer sub-divide. It’s why our next move is to get Adam some form of immunotherapy, the antibody treatment that has proved to be a major breakthrough in the fight to prevent relapse in neuroblastoma patients.

Of the two main possibilities we were looking at the favoured option was a new trial opening up in America using a humanized 14.18 antibody + GM-CSF + cis-retinoic acid. The other was the chimeric (part-human, part-mouse) 14.18 antibody + Interleukin 2 trial in Germany. Adam’s FDG-PET scan now makes it less likely we will be able to go to America for treatment. The trial there requires active disease as evidenced by biopsy. With a clear PET scan that’s something that becomes less likely. It’s also unclear at the moment whether or not there is a site that could be biopsied at all. That’s down to the surgeons at the Marsden, and there was even mention of asking the Royal National Orthopaedic Hospital for an opinion if necessary.

Earlier today Adam was back at the Marsden for a Gallium Octreotide scan. This is another scan that he’s had for the first time. It’s similar to an mIBG scan, but the radioactive tracer is attached to a substance that is taken up by a different set of receptors on the surface of neuroblastoma cells. Theoretically we should expect, and indeed probably hope, to see the same sort of uptake on this scan that we see in the mIBG scan although the intensity may vary. That would be consistent with what we think is going on.

And so there you have it. I know my updates are becoming ever more complicated … but then so is the situation we find ourselves in.

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