Convection enhanced delivery of chemotherapy to paediatric brain stem tumours

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Published: 8 Feb 2016
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Prof Steven Gill - Southmead Hospital, Bristol, UK

Prof Gill talks to ecancertv at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.

In the interview he discusses early clinical experience of intermittently delivering carboplatin directly to paediatric brainstem tumours using a novel implantable neurosurgical device.

The device consists of four very fine catheters that are implanted deep within the brain using a dedicated robotic technique.

Chemotherapeutic drugs can then be injected directly into the site the tumour via a technique called convection enhanced delivery (CED).

The device was originally developed for delivering a protein therapy to adults with Parkinson’s disease and is now being tested in children with diffuse intrinsic pontine glioma (DIPG), a tumour that is not amenable to surgical resection.

I focus very much on DIPG because it’s actually one of the most challenging areas in brain cancer in kids. It really came about because I developed a drug delivery system for treating Parkinson’s disease and I was approached by a colleague who said we have a child who has got this condition, would your system work in this type of environment? Sure enough, you could deliver anything down this device. So we embarked on a treatment on compassionate grounds and found that we could deliver drugs safely to this critical area. That fairly rapidly picked up with more and more children being referred to us to try and treat them. We’ve used a fairly conventional chemotherapy drug, carboplatin, and actually it did require quite a lot of work in the background beforehand in looking at the toxicity and safety of that and getting MHRA approval and then ethics approval and things like that to actually treat these children.

I guess for the first time in this disease we’re seeing the tumours being controlled by a chemotherapy agent. When children had radiotherapy and then there’s the inevitable progression within months we are now being able to get that under control. So that has been a fantastic start, really, to really the potential of delivering much more specific and targeted drugs.

Can you tell us about the device that your group has developed?

The biggest problem we face in neurological disease is getting drugs across the blood-brain barrier. In Parkinson’s disease there is a protein, a naturally occurring protein called GDNF, and experimentally that has been shown to repair nerve damage and effectively reverse animal models of disease. To get a protein across the blood-brain barrier you have to deliver it directly and then not only get it in there but actually drive it out to cover the appropriate volumes. This is something I’ve worked on for something like ten years or more and this has required developing quite sophisticated equipment. So we use robotics to deliver the devices because they’re very, very tiny, the catheters are just over 0.5mm in size, and they need to go over quite long distances in the brain. So to do that is a challenging thing to do. I’ve worked in collaboration with a company called Renishaw who are an engineering company at the top end of being able to deal with tiny things, both manufacture them and quantify them, measure them. So they have really worked in partnership with me to develop the technology which includes robots, the software and the devices to deliver into the brain. We’ve now brought that into a clinical study in 42 patients and now is the time I guess we can start looking at oncology which is a huge area where we really are not making any progress at all. There are many drugs now that you can start looking at that previously you couldn’t because you simply couldn’t get them across the blood-brain barrier.

So in a way it’s an exciting time for us. We’re now looking to collaborate with people with the know-how in these areas. So this meeting that we’re at now has been very helpful in that.

Has the device been adapted for use in children?

No, the catheters have to be very tiny anyway so they’re 0.5mm in diameter, so they’re very, very tiny. So there hasn’t really been much in the way of changing the technology at all, it’s exactly the same. The differences are skull thickness and these more technical things but a child’s skull is only maybe 1mm to 1.5mm thick whereas an adult’s is up to 1cm. So from a technical point of view or a surgical point of view there are some issues but we’ve tackled those.

What results have been obtained to date in DIPG?

We’ve seen, surprisingly, shrinkage of the tumour where we’ve been able to infuse. We’ve learned how to infuse quite large volumes, so in other centres around the world they may deliver say 1ml or 2ml, we can deliver 10ml or more in a day. This is down to designing the catheters which can safely infuse over large volumes under low pressure rather than a point source of high pressure. So there are some technical aspects there. Also because of the accuracy with which we can deliver catheters we can do it very safely so we can put lots of catheters in, we can put four catheters into the brain stem quite safely. That means we can get an efficient delivery over the whole volume. So we’ve seen shrinkage of tumours in the majority of our patients and with that prolonged survival.

Why was carboplatin selected?

The choice of the drug was carboplatin doesn’t cross the blood-brain barrier. It certainly is effective against gliomas in a petri dish. It’s water soluble. So those are important things. So when you put this rather toxic drug into the brain it doesn’t cross out and therefore there are no systemic side effects from it. It stays in the brain for a long time and this thing called the area under the curve, there’s a long exposure time to a drug that actually proves to be pretty effective. It has been surprisingly effective in otherwise very resistant disease.

What about the safety and practicalities of the approach?

It’s probably not as severe as radiotherapy, to be honest. So normally there is a repair mechanism of DNA so that’s a process that continues certainly in the cells, the normal cells. So far we’ve done 20 infusions at what would be a massive dose in children so simply to get that concentration across the blood-brain barrier you’d have to give ten times the tolerated dose. Children wouldn’t survive that giving it systemically. So the actual dose in the tissue is huge by normal standards but extremely well tolerated and we’ve not seen any concerning long-term effects from that.

When do you hope to move into clinical trials?

We’ve treated so far six children on compassionate grounds while we’ve been trying to raise money and we’ve been raising money through a charity called Funding Neuro really specifically for this trial. They have raised something like £650,000 in a very short time. So this has been a very efficient way of raising money, probably faster than many of the routine pathways. There has been a lot of public support, so this has been on the TV and on the radio and it’s on the web so there’s been enormous generosity from people and patients’ families. So we have raised both the awareness of this disease and the money. One child who was referred to us for compassionate treatment two weeks ago, the family needed to raise money because there is no support, and they went on TV South at six o’clock in the evening and by ten o’clock in the evening they’d raised £40,000 just by public donation. So this is possible. So that’s what we’ve relied on, this sort of thing happening, up until now. But we’re now ready to run this 15 patient trial. Our objective is to prolong survival, we’re not going to cure the disease but we would prolong survival and these children would hopefully have a good quality of life because this isn’t toxic chemotherapy that we’re used to with hair falling out and them being sick, they just sit and watch TV and then go home. So it’s a very, very different approach, they get a good quality survival and we’ve certainly extended life in certainly one child by at least a year, others by many months so far and five out of our six children are alive and still receiving treatment. So this is definitely doing something.

Could you foresee this being a cure for DIPG?

I guess you have to believe it’s possible and I think it’s going to be an immunotherapy of some form where your body recognises the tumour as foreign and seeks it out. At the moment the therapies are not really at the point of safety, I don’t think. So what we’re doing is simply using conventional methods to shrink the thing down and we’re controlling the disease where we can deliver. But, as with all cancer, cells migrate away from where we’re infusing. Yes, we could put more catheters in and, yes, we could do this but ultimately you want something a bit more sophisticated, really, to seek out or get the body to seek out and destroy the tumour cells.

What is your take-home message?

We now have the ability to treat neurological disease with a whole range of different drugs which were never available because they wouldn’t cross the blood-brain barrier. And we can safely deliver those where they need to go. So that actually is quite a big step at this point. Of course we want the cures for all these things but this is an important step towards it.

What about the wider use of the device?

This is currently what’s called an in-house device so the manufacturer is formally my hospital, it’s made by a company on their behalf. This other company called Renishaw wish to then make it into a product in time but they have to go through quite a long process of manufacturing their own device and I think that is in progress. So it will be more sophisticated, perhaps, than the one we have. But all these things take time and it may be, say, a year away. They’ve got to do their own trials in other areas so that, I think, will happen. But in the context of trials it is possible to use experimental devices as well. So I’m hopeful that other people will be able to use the same thing and we can start some bigger trials looking at different things.