No news is no news …

It’s that time of the week again, time for my regular update. There really isn’t anything to say on the treatment front. Nothing has moved forward since last week; we haven’t even received dates for the two additional scans yet. I’ve gone into hassle-and-chase mode on the basis that Adam is now D+80 post-transplant, and he will be off-treatment until we start in Germany or America. Without the scan results we can’t make a decision on whether or not to biopsy, let alone where we are heading off to. I’m just hoping that when we do get dates they are not two or three weeks hence, otherwise I’ll have to shift up into make-lots-of-noise-and-cause-lots-of-fuss mode. If needs must.

Adam has remained generally very well in himself, and the great weather over the Easter break definitely agreed with him. We were back down at the coast where the kids could get out on their bicycles, and spend time playing outside together, and with friends. On Saturday we took a trip to West Wittering where there is a lovely sandy beach. Needless to say it was absolutely mobbed, but we didn’t (as planned) arrive until later in the day so we missed the majority of the queues. Alan, Adam’s uncle, had brought an inflatable dinghy along, and naturally Adam was the first to have a go. I’m sure there were a few admiring glances as Adam stripped down to his pants and hickman line so we could wrap him in cling-film, to at least offer some protection against the sea water. He thoroughly enjoyed it, although he was a little unsure at first when he took a couple of bigger waves over the side on the way out. Thankfully we had no major catastrophes though; no capsize or boy overboard.

On the alternative treatment front we are currently having blood and stool samples analyzed by the lab once more now that Adam is well past high-dose. The results of these may give us further areas to work on in terms of Adam’s general health. Our goal is to make him better able to fight his cancer from within, and also to reduce side-effects and recovery time from conventional treatments. We should have the results in a week or two.

'Thank You' and 'Yes' ...

One thing we are incredibly fortunate about is that through the overwhelming generosity of people who have supported Adam's Appeal we don't have to worry about financial considerations at the moment. That said, once we leave the UK we are opening ourselves up to an indefinite period where we are liable for all treatment costs; and we know from the experience of others how quickly they can escalate. Not surprisingly the cost of taking Adam to America will be much higher than if we go to Germany. So thank you once again to everybody who has donated, supported, organised, collected, run, walked, cycled, baked, cooked, packed bags, washed cars, written letters, spoken to employers, and so much more besides. And thank you also to those people who have indicated that they are intending to help Adam's Appeal in the future. If you are sat wondering whether or not Adam (and I'm sad to say plenty of other children like him) still needs your help the answer I can assure you is a most emphatic 'yes'.

The plan to determine the plan ...

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.

Written on location ...

Not much of substance to report this week really. We are away at the caravan at the moment getting some rest and relaxation (within the limits of what's possible with three children), and enjoying some family time together. Obviously I have taken a lot of time off work over the past year-and-a-half, but not much of it could be classed as 'holiday'.

I can't overstate how good having the caravan has been for us. It's such a lifeline to be able to get away from everything (but still be close enough to home to be within our comfort zone as far as Adam is concerned). The biggest benefit of all is we can live the same lifestyle, eat the same foods, do almost all the same things for Adam that we do at home. I just wish the kids would get with the program and stay in bed longer in the morning. Instead they fall naturally into the habit of going to bed later and yet waking up at the exact same time as usual. Bad, bad, bad.

Adam himself is doing great at the moment. I am aware that may seem at odds with recent posts, but apart from the first couple of months after diagnosis it's been like this throughout. If you lined up Adam's scans with a group of other NB children he might appear clinically to be in relatively bad shape. However, if you saw him, and observed his behaviour, you wouldn't suspect there was anything wrong with him. He's not quite back to how he was prior to high-dose, but he's not far off. Now the weather is improving, and the days are getting lighter, he's been spending more time playing outside with Jake and Jess. Consequently his general level of fitness, which took a big knock as he went through high-dose, has started to return. His energy levels and stamina are noticeably improved from what they were just a week or two ago.

On Tuesday we had a day at Chessington World of Adventures before travelling down here. We all had a great time, and Adam particularly enjoyed (1) me getting wet on bubble works after he'd assured me the water wasn't real, (2) me getting scared when he made the pink elephants go really high after he'd assured me we would stay low, and (3) me screaming with fear on the runaway train after he'd assured me that the second time round it only went 'really slowly'. You get the idea ... all in a paternal day's work.

Adam's blood counts have plateaued over the past fortnight. Hb is 10.3, neutrophils are 1.3 and platelets are holding around 80. Though not normal by any means the numbers are respectable considering how much treatment Adam's had, and we are now back to weekly bloods. I think in total Adam had 6 or 7 platelet transfusions since high-dose, which is a lot fewer than we would have forecast a few weeks ago.

We are still waiting for some more information from America before we can make a decision about where we go next. It's also been suggested that it might be useful for Adam to undergo some additional tests, although we don't know what, why or when yet! We're doing a good job of not fretting about how things are going to work out logistically over the next six to twelve months. It's going to be a pain in the proverbial for sure, but we'll muddle through and get it done. In the meantime we are just getting on with life one day at a time. Much like everybody else really.

It occurred to me this morning ...

... that yesterday's update was somewhat incomplete. Not where the facts about Adam are concerned, but in a more general sense regarding where things are at now, and where we might be heading in the future.

That neuroblastoma is deadly is without question, but it also has a certain strangeness. It is one name but many diseases. It's not very well understood, and despite all the advances in medicine over the last couple of decades there remain lots of unknowns. It has an almost entirely benign form, and an ultra-aggressive form at the same time. The spectrum in between is vast, and there are very few absolutes. I find it incredibly difficult trying to understand enough to believe we are making intelligent and informed decisions for Adam, whilst at the same time accepting that I probably know next to nothing.

Here is some basic information to begin with; neuroblastomas are highly malignant tumours that originate from tissue that form the sympathetic nervous system. Ganglioneuromas are benign tumours  that originate from the same. One is a mature form of the other i.e. neuroblastoma cells can mature into ganglioneuroma cells. Ganglioneuroma cells can dedifferentiate to become cancerous. Tumours can be formed by a combination of the two types of cells - this is referred to as ganglioneuroblastoma, where immature neuroblastoma cells are either mixed in with, or form clumps amongst, ganglioneuroma cells. It's already a minefield, and we've barely gotten started.

For many many years all children, including newborns and those very young, were treated the same. As though all neuroblastomas were the same, distinguished only by a few established markers such at N-MYC amplification, and by whether the disease was confined to a localized tumour or had metastasized to distant sites. All children were given intensive treatment, and some undoubtedly died as a result of these medical interventions rather than neuroblastoma itself. Subsequently it was discovered that in a number of very young children (usually < 12 months old) the most appropriate course of action was to do nothing, to adopt a watch-and-see approach. For in many cases amongst this particular group neuroblastoma spontaneously regresses and disappears without any treatment at all. As far as I understand it the why and how of this spontaneous regression remains unknown, but is assumed to be related to their early developmental stage. Of course there are now children for whom a wait-and-see approach is taken whose neuroblastoma does go on to become progressive. For them early intervention or tumour resection would, with the benefit of hindsight, have been the best course of action. This world is not, and never will be, perfect.

There is also another group of neuroblastoma patients; children for whom intensive and continued treatment does nothing to reduce their observable disease load. These children are collectively referred to as refractory. More and more clinical trials in the United States are being opened specifically to target refractory and recurrent/relapsed neuroblastoma. They are hard to treat successfully and the prognosis is generally very poor indeed. Treatment after frontline therapy has failed is an area where our NHS is way behind medical institutions across the Atlantic. Adam is in this refractory group.

It would seem natural and obvious that being in the refractory group is a universally bad thing, but it's not necessarily always the case. Within this group there is another smaller subset of children, albeit the exception rather than the norm, who become long-term survivors despite never ever reaching the panacea of NED (No Evidence of Disease). There are some of these children in the UK, there are plenty more in America. In general they are (re-)diagnosed with chronic neuroblastoma. It is assumed that their 'disease' has either undergone maturation or otherwise taken on a more indolent form. In this state, whilst it will still light up on MIBG scans, it is completely impervious to chemotherapy, radiation, and whatever else may be administered to try and combat it. The one thing these children do have in common with the 'wait-and-see' group is that their lives can be destroyed by endless rounds of unnecessary treatment.

So you can now really begin to see how difficult this really all is. To the point of being practically unfathomable. There are children who have a remarkable response to induction therapy - 80 days of on/off chemotherapy and all their disease completely disappears. And then back it comes, twice as fast, twice as aggressive, and there is nothing that can be done. There are children who respond to frontline therapy, go through high-dose, radiotherapy, immunotherapy having no evidence of disease and yet relapse days, weeks, months or years after. Most relapse within two years, but within five years is not uncommon and even beyond that remains a definite possibility. There are, of course, those who respond to frontline therapy and go on to become long-term survivors. Then there are those who have refractory disease, who remain stable for an extended period of time before eventually succumbing to progressive disease. And then there are long term survivors who move from childhood to adulthood with the same level of 'disease' that they had when they stopped treatment. Who, if they were scanned today would still look identical to a stage 4 neuroblastoma diagnosis.

As time has gone by I've got to wondering how long Adam had been living with neuroblastoma before he was diagnosed. Had it been with him all his life? Are we at this juncture because Adam has had slow growing disease for many years? He's never had a dramatic response to anything that's been pumped into him, and generally speaking cytotoxic agents used in the treatment of cancer tend to work on faster growing immature cells that are rapidly dividing. That's why they cause hair loss and bone marrow suppression because of their indiscriminate nature. Set against that his presentation on diagnosis with extensive bone marrow, lymph node and skeletal disease, coupled with his N-MYC amplification and the fact that his primary tumour wasn't ganglioneuroblastoma, is suggestive of something altogether different. Did he have a slow growing form of neuroblastoma that mutated into an a more aggressive strain? Are we treating the latter so that we remain with just the former? Is it even possible? So many questions, but the only truth is that whatever answers we come up with they are mere supposition, and we'll never ever know the true story.

So where does this leave Adam, and the prognosis for his future? We have to believe he is in that small subset of children who will go on to long-term wellness despite what shows up on his MIBG scan. I think we've come to a point where we can no longer harbour false hope that Adam will ever be clear in the conventional sense. We haven't reached a point where we have no hope, but rather we now have a different hope. Our baseline has moved from being no disease to being no more disease. It doesn't seem such a monumental change when thought about in those terms, does it? Whilst there is no progression, and no new disease in other areas, we can still have hope, we can still believe. It may not be the most probable scenario there is for Adam's future, but it's not one that is entirely beyond the realms of possibility. As one of the nurses at the Marsden said to us when we first started out on this journey and began to learn some of the awful truths about neuroblastoma - "Even if statistically the chance of long-term survivorship was only 1% you have got to believe that Adam will be in that 1%." And she was right. Hope that is not false hope, however small, is a very precious thing indeed.

Scan results …

The last two weeks have been pretty tough; waiting to find out where things are at after Adam’s bone marrow tests, CT and MIBG scans. I’ve lost count of the number of times we’ve been down this road over the past year-and-a-half, but for some reason this time the purgatory was worse. Or maybe it wasn’t really, maybe it’s simply that every time seems worse than before. It’s being in the moment, filled with fear and uncertainty, versus looking back all-knowingly after the fact. Each and every time the fear gnaws away inside your head saying ‘This time it’s going to be bad. This time the luck’s going to run out.’ I’m sure people that have trodden this road themselves will know what I mean.

This morning we received the results.

Stable disease.

Despite all the chemotherapy he’s had; despite two rounds of high-dose radiation therapy, despite high-dose chemotherapy with stem-cell rescue, Adam’s MIBG scan shows the same disease burden he's had for the past year. His scans continue to light up throughout his spine, pelvis and at the top of both femurs. We've been told, more or less, that in all likelihood Adam will never be 'clear' of whatever it is that he has got, and at best whatever it is that lights up on his scans will always be there. Moreover, there is currently no way to determine, other than through the passage of time, what it is. If it’s mature cells he could live with it for many years to come. If Adam is still alive and well in 30 years time we will be able to say with some degree of confidence that it isn’t, and wasn’t, active neuroblastoma. That’s the prospect we are now faced with.

The CT scan of Adam’s abdomen, specifically in the region of his primary tumour, was completely clear. His bone marrow aspirates were also clear. The bone marrow trephines showed a very small percentage of ‘abnormal cells’ on immunological testing. However, their presentation was not consistent with Neuroblastoma, and by all standard measures the results from the trephines are considered clear as well.

Whilst I had hoped everything would somehow miraculously disappear, and as much as I worried that things would show up that weren’t there before, this is the outcome that I very much expected. It means we have to get our heads around the fact that unlike normal cancer patients the ultimate aim of having no evidence of disease is one that we realistically have no possibility of reaching. The goalposts have been moved. At some point we will have to stop treatment and just 'hope' that what's left is not malignant. However, we're not at that stage yet. We’re not even close.

We have begun talking to Adam’s doctors about where we go from here. Our Consultant and Professor Pearson at the Royal Marsden are being supported by experts from other countries. Our most likely next move will be to take Adam to either Germany or America for some form of immunotherapy, and at the same time start him on a course of oral retinoic acid. This does nothing for what lights up on his MIBG scan, it's to try and prevent him relapsing in other areas. It's not beyond the realms of possibility that we will do 6 months in Germany and then transfer to America for 6 months, so that we do two treatments back-to-back. We should have a decision in the next couple of weeks, with treatment starting sometime in May.

In one sense this is an odd update. Normally I have little difficulty with the tone of what I’m writing. I mean I have no idea how it comes across to other people, but (knowing what it is that I’m trying to say) it’s usually clear to me when I look at it. Reading back what I’ve just written I don’t get that. Is this good news? Is it bad news? Well, it’s good and bad news really. Most of it is what, deep down, I expected to be writing. Our most optimistic forward forecast is that we have at least another six to twelve months of difficult times ahead, emotionally, practically and logistically followed by a lifetime of uncertainty. At the same time we’re ever thankful that we have our middle-sized boy still with us, and that at least we do retain some hope for the future when many others do not. Immunotherapy is no walk-in-the-park, intense pain, dangerously low blood pressure, hives, severe fluid retention - all manner of side-effects can, and more often than not do, occur. At the same time Adam has tolerated a multitude of treatments to date remarkably well, with a courage and maturity that belies his years. So it’s a mixed bag I suppose; there are both positives and negatives to be found depending where you look.

Flat - that probably sums it up best.