Apologies in advance because this is complicated. It's complicated because the situation we find ourselves in is complicated. As a consequence, it's more full of medical speak than ever before, but even if a lot of it goes over your head at least you'll (hopefully) get a flavour of what we are wrestling with right now. Think of it as more of a brain-dump than a thoughtfully constructed narrative ...
Here's where we're at; we are primarily considering two possible courses of action.
The first option is to take Adam to Germany for the ch14.18 + IL2 antibody (immunotherapy) trial. The primary role of antibody treatment is to consolidate remission, to mop up any minimal residual disease that remains undetectable but almost certainly exists and which if left will, sooner or later, result in a relapse. However, the scope of its use is being expanded to see whether or not antibodies can be effective in treating children who still have disease left after induction therapy. Unlike the groundbreaking U.S. trial (ch14.18 + IL2 + GM-CSF), that remains open only for children who achieve a remission having reached high-dose within nine months of diagnosis, the German trial is accepting children with refractory and relapsed neuroblastoma. Adam is eligible for, and has been accepted into, this trial if we decide it's the right thing to do.
The second option is to take Adam to America, most probably Philadelphia for a different type antibody trial. This involves ch14.18 + IL2 + GM-CSF, but the ch14.18 and IL2 are manufactured as a fusion protein. The cytokine (IL2) is fused onto the GD2 antibody (ch14.18) so it is taken direct to the neuroblastoma cells. The idea / hope is that this intrinsic coupling will result in a more potent and effective treatment. Results from a phase I trial of the ch14.18 + IL2 fusion protein alone were very encouraging, however a more recent phase II trial of the same was less so. The new trial, which opens in May, adds GM-CSF and 13-cis retonoic acid (accutane) as additional components alongside the fusion protein, hopefully resulting in improved efficacy compared to the previous trials.
There are other possibilities that we could look at more closely, but they are generally treatments in early-stages of development; phase I and phase II trials that may or may not become more standard treatments in the future. There may come a time when we turn to these as our main (or indeed only) hope, or if one of them emerges as a potential major breakthrough in neuroblastoma treatment, but I just don't see that we're there yet. One thing that is off the agenda at this moment in time, and whilst Adam's disease remains 'stable', is more intensive treatments that would have a significant adverse effect on Adam's fragile bone marrow. Having undergone both MIBG therapy and high-dose chemotherapy since the turn of the year his body needs time to recover. I would have liked to have been able to seriously consider humanized 3f8 antibody treatment at Memorial Sloan Kettering in New York, but this won't be available for another 3 to 6 months. Still it's something we may come back to in the future.
The obvious question then is why immunotherapy? Why are we considering putting Adam through a treatment whose primary (and only proven) purpose (thus far) has been to consolidate remission by clearing up minimal residual disease? It's a fair question. An important thing to keep aware of is there are no right answers to the situation we now face with Adam. There are no treatments proven to clear his remaining disease burden as seen by MIBG scan. There are, however, wrong answers. For example, all the evidence from the early phase trials of the ch14.18 + IL2 fusion protein indicate that it is ineffective against bulky tumours. If Adam had solid tumours or soft-tissue disease we shouldn't, and wouldn't, be considering it at all. Similarly, some of the oncolytic virus trials that are opening up in America involve direct injection of the virus into the tumour site, making them entirely inappropriate for the type of disease that Adam has. It's one of the defining characteristics of metastatic neuroblastoma that it has so many different manifestations; bone marrow infiltration, bone lesions which themselves can be either diffuse or well defined, infected lymph nodes, soft tissue disease, lung and liver metastases. A treatment that shows efficacy against one of these types of disease often has no benefit whatsoever against others.
The fundamental question, and the reason why we are most likely going down the immunotherapy route, is what are we hoping to achieve? Are we still trying to clear Adam's visible disease and get him to a point where he has clear scans? Or are we (for now at least) accepting that disease as stable, hoping it stays that way, and trying to prevent the cancer from taking hold elsewhere. It would be unrealistic to assume the cells that are observable on his MIBG scan are the only ones that remain in Adam's body. If a child who is NED (No Evidence of Disease) after induction therapy still has minimal residual disease that cannot be detected on any scans, it's safe to assume Adam has neuroblastoma cells lurking around in other places too. If these are not dealt with they could result in new areas of full-blown disease, and when neuroblastoma returns it often does so bigger and badder than before. Ideally, of course, we'd like something that might do both - clear the visible disease and wipe out the residual disease too - but that might be hoping for a little too much. There are no magic bullets.
The bottom line is there are no treatments that have been proven to clear children like Adam. The most effective, and most widely used, is I131 MIBG therapy and Adam has done that ... twice. Technically he is permitted to have a third administration, but given that the first two appear to have done nothing for him there would seem to be little justification in putting him through it yet again. If we assume, for one moment, that what lights up on Adam's scans is matured cells that have differentiated then immunotherapy becomes the obvious choice for what to do next. But we don't know that for certain, do we? And therein lies the crux of the matter. If it's MIBG-avid but not active neuroblastoma then choose whichever we believe will be the better at dealing with residual disease (we can't have the treatment that has been proven to deal with residual disease - it's just not available to Adam; not anywhere; not at any price). If it's MIBG-avid and it's active neuroblastoma the results from the phase I clinical trial would suggest the fusion protein is the best way to go in the first instance. It's possible we could do both treatments one after the other, but that very much depends on what adverse effects they have on Adam's body, which of course we won't know until we go through it.
So far it's as clear as mud then, and just to make matters worse only children with active disease are eligible for the new fusion protein immunotherapy trial. And whilst Adam has extensive MIBG uptake that is no longer (as per all my comments about mature or differentiated cells) conclusive proof of active disease. Which brings me to the title of this post; the plan to determine the plan ...
Adam is going to undergo two more scans; an FDG PET scan, and a Lutetium Dotatate scan. Whilst neither of these are currently part of the standard tests for neuroblastoma they may have something of relevance to offer in our current deliberations. The FDG PET scan provides an image showing uptake of glucose, which is indicative of the metabolic activity in active cancer cells. The Lutetium Dotatate scan is similar to an MIBG scan but the radioactive tracer attaches to different receptors on the surface of neuroblastoma cells (somatostatin receptors for those that are interested!).
If both scans, and in particular the FDG PET scan, show positivity in the same way as the MIBG it will give us more evidence that what we are dealing with is active neuroblastoma. Then perhaps we would be better advised to head to America for the fusion protein immunotherapy trial in the first instance, and whatever else they can offer after that. Before we could do that, however, we would still require conclusive proof of active disease, and for that it would be necessary for Adam to undergo a bone biopsy. And for that biopsy to be positive for neuroblastoma. I hate the idea of a bone biopsy; the procedure itself, the pain and discomfort afterwards, the idea that performing it might in itself help re-ignite the cancer, and on top of all that we still might not get a conclusive result. Effectively we'll be on a hunting expedition trying to find some active neuroblastoma cells that will buy Adam a ticket to the U.S. trial.
On the other hand, if the additional scans are negative it would lead us to believe more strongly that the MIBG is being taken up by mature cells and we should be concentrating on immunotherapy as a means to deal with the minimal residual disease that undoubtedly exists within Adam's body. Whether that necessarily means Germany over America though is something of which I'm not entirely sure at the moment.
One final consideration to throw into the mix is this. As many of you know we've been pursuing a very different lifestyle for the past 9 months or so. One that involves us going organic as much as possible, cooking our food almost exclusively from scratch, eradicating the use of refined sugar and dairy from Adam's diet, using a daily routine of food supplements such as Avemar, Life Mel, Vitamin-D and Omega-3, removing harmful chemicals and toxins from our house, and much, much more besides. We know it's going to be very difficult to replicate this abroad. I refuse to believe it's impossible though, and to that extent I remain indifferent from a logistical perspective as to whether we end up going to Germany or America. We will take Adam to wherever we need to so that he can get the treatment that we believe is the best for him at this time. Our decision making process will be no different than it would have been had everything been available on our doorstep at the Royal Marsden. We will worry about the practicalities once we've got a plan ... the actual plan.