Intra-arterial chemotherapy methods for CNS tumours

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Published: 8 Feb 2016
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Dr Monica Pearl - The Johns Hopkins University School of Medicine, Baltimore, USA

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

In the interview she discusses her work on intra-arterial chemotherapy for central nervous system tumours.

Dr Pearl explains that her research largely focuses on diffuse intrinsic pontine gliomas (DIPG), which is not amenable to surgical resection.

Getting drugs across the blood-brain barrier to treat this paediatric brain tumour remains a challenge and one approach Dr Pearl and colleagues are investigating is intra-arterial administration.

They have started a pilot study in children with recurrent DIPG and so far two of a planned five children have been recruited.

So far they have seen that intra-arterial administration is technically feasible and appears well tolerated.

Specifically I work with DIPG, diffuse intrinsic pontine gliomas, and what we have seen described earlier today is just located within the pons, that makes it a difficult surgical access. So I’m not a neurosurgeon but because it’s not surgically amenable to resection you really try these other treatments. The intricate blood supply that goes to the pons, intact blood-brain barrier and really the lack of imaging for a drug biodistribution, those are the current challenges that we face now.

What research have you been doing to try to address these challenges?

We’re trying to address it on both the clinical and research fronts. From a clinical perspective we have a pilot study that’s registered on clinicaltrials.gov and it’s for the intra-arterial chemotherapy for recurrent DIPG. In that pilot study we administer intra-arterial melphalan, a chemotherapeutic agent, directly into the basilar artery. The idea stems from our research with retinoblastoma and success with giving local chemotherapy targeted to the tumour. So by enabling more precise delivery and more local delivery to the artery that supplies the pons and the brain stem we’re hoping to achieve better delivery that way.

Why look at recurrent DIPG? How have the children been treated before entry?

Along with standard of treatment most children are treated with radiation therapy and then they get whatever regimen that people are trying now. But we chose the time of recurrence for our study for the intra-arterial delivery because typically at the time of recurrence the tumours manifest enhancement on MRI. The enhancement on MRI is an indication that the blood-brain barrier is disrupted in some fashion. So with using the intrinsic nature of blood-brain barrier disruption at the time of recurrence we’re hoping that the intra-arterial delivery methods will enhance that.

What is the technical research you are doing?

Part of the issue is we can deliver the drug easily from a technical standpoint through standard neuro-interventional procedures with guide catheters and micro-catheters and go selectively to the basilar artery which is right there where all the blood supply is. But at the same time once we deliver the agent you don’t really see it going into the parenchyma and crossing the blood-brain barrier. So it’s this lack of the drug biodistribution imaging.

From the research standpoint I work with my colleagues, they’re here also with me today, Drs, and we work to create this neuro-interventional MRI platform. So from an intragraphic standpoint I can place the catheters into my selected targets and then we transport our animal to the MRI scanner, research scanner. Then when we inject contrast or any kind of agent through the micro-catheter we’re able to see and predict where is the perfusion territory. Then we are able to titrate based on the rate of flow or catheter location, where exactly is it going to go. So it gives us that visualisation of the parenchyma to be perfused. So that will allow us to both predict the area of perfusion, if we want to disrupt the blood-brain barrier with mannitol we can do that, and then afterwards we have actually given the drug that we’re giving clinically and we can see from our studies that it does cross and it correlates with the area that we’ve predicted. So that’s really an exciting area of research for us because we have an animal model that simulates the same blood supply and that we’re able to use these MRI techniques to predict and titrate infusion rates so that you get a more localised territory.

What is the evidence behind using intra-arterial chemotherapy in children with brain tumours?

We’re the first group to be doing intra-arterial chemotherapy specifically for DIPG. In the interventional neuro-radiology community in which I work there are a few centres who do intra-arterial chemotherapy for other brain tumours but it’s not widespread and we’re the only ones who do it specifically for DIPG because we have a specific answer to address.

Can you tell us more about your study in children with DIPG?

It’s pilot study so that means initial small study at first. We’ve only had two children enrolled so far and our target is five. The reason why it’s small is because we really want to see and document that there’s initial technical safety and tolerability of the procedure because we’ve seen many of these children, their brain stem is diffusely enlarged and we don’t know by really giving the chemotherapy right directly at that target will they be able to tolerate it. So we’ve seen and demonstrated the technical safety and initial tolerability but there are so many questions that remain unanswered as far as drug of choice, dosing regimen and treatment strategy. But initially we’ve seen the tolerability and technical safety so that’s the first step.

How is the intra-arterial therapy actually given?

No, it’s similar to any of our standard neuro-interventional procedures, so cerebral angiography. Patients are asleep and we go through the femoral artery in the leg and we bring up a catheter into either vertebral artery, it will depend on which one is bigger or if they’re equivalent or co-dominant we would go on one side one session and one side the other because ultimately the two vertebral arteries join to make the basilar artery. Then we’d bring a small micro-catheter through that catheter in the vertebral artery all the way up into the distal basilar artery. Then I infuse the chemotherapy by hand and it sprinkles the territory that is supplied from the basilar artery and then all those innumerable little branches from the basilar coat the pons.

This is a lot less invasive then than other approaches being suggested?

Absolutely, absolutely. So I think that there is a lot of convection enhanced delivery that was discussed today. They have seen some promising results but it is more invasive because that involves catheter placement through the brain. Ours is intravascular, through the blood vessel and then when we’re done we take everything out and then we just hold pressure at the femoral axis site. So from a minimally invasive standpoint that is a huge advantage but what remains for us to see is is it efficacious. I think a lot of that is going to have to deal with improving the imaging, so that MRI platform to see where is the drug going. Then also what would really be helpful would be after treatment would be tissue for histological analysis to determine was the tumour treated well. If we know it was treated well or responsive then we could say that this method allowed the drug to enter and it did have some efficacy. But that’s really difficult to know now in the absence of histology and advanced imaging.

What is the ultimate therapeutic goal?

Ultimately try to cure it. We would need the optimal drug which is, I guess, the whole basis of this conference. Choosing the right drug or other agents, MRNA viruses, I guess you could just say therapeutic agent because it doesn’t have to be a chemotherapy agent. But it’s combining everyone’s specific areas of expertise, the delivery routes, which one is going to be best, and then targeted agents.

What further research will you be doing or needs to be done?

We are currently working on improving our imaging of the agents. So we are continuing with our clinical trial of delivering the chemotherapy and seeing if the children tolerate it and if we see some initial efficacy. At the same time we’re improving our imaging on the MRI side so that we can at the same time as the procedure watch the drug go through and then being able to detect the drug in the brain parenchyma. Because then you can know is it a failure of the drug itself or is it a failure of the delivery method that the drug doesn’t get to the target.

What is your take-home message?

I would say that intra-arterial chemotherapy for DIPG is a promising alternative and we have shown that it is technically feasible and initially tolerable and from a technical standpoint safe. But there are so many questions that need to be addressed as far as correct drug, dosing regimen and treatment schedules. But one way that will really help doing that and a start is to develop better imaging and these combination platforms, like neuro-interventional platforms, where you combine multiple modalities. I think that’s a great place to start.

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