hospital beds on a ward

Sharing learning between childhood leukaemia and brain tumour trials

 

 

Over the last 50 years, advances in surgical procedures, clinical understandings and targeted treatments have changed the prospects of many cancer diagnoses from terminal to treatable. However, this progress is not evenly distributed across the many different types of cancer, and nowhere is that more keenly felt than in cancers affecting children.  How might the advances and insights in treating blood cancers benefit patients with brain tumours?

 

To answer that question, Dr David Walker and Dr Chris Halsey talk about their research connecting trials and treatments across disease types, for the benefit of all patients.

 

Read more: http://dx.doi.org/10.1016/S2352-4642(19)30333-5

 

Image credit: Venusvi/Shutterstock

 

 

 

This transcript is automatically generated.

00:00:12 Will

Over the last 50 years, advances in surgical procedures, clinical understandings and targeted treatments have changed the prospects of many cancer diagnoses from terminal to treatable. However, this progress its not evenly distributed across the many different types of cancer, and nowhere is that more keenly felt than in cancers affecting children.

 

To even the playing ground, there’s a lot that can be learned from searching – not just deeper within any one disease – but across the whole spectrum of cancer.

 

Take leukaemia for example: How might the advances and insights in treating blood cancers benefit patients with brain tumours?

 

To answer that question, I am speaking today with Dr David Walker and Dr Chris Halsey about their research connecting trials and treatments across disease types, for the benefit of all patients.

 

 

00:01:07 Will

Hello to you both. If we could start with Doctor Halsey, could you tell us maybe a bit about yourself and your background?

 

00:01:14 Dr Halsey

I’m Chris Halsey. I’m a clinical senior lecturer and also a honorary consultant. Paediatric haematologist up in Glasgow so I split my time between working and running a research lab in the Institute of Cancer Sciences at the University of Glasgow and then also having.

Clinical commitments in the Royal Hospital for Children looking after children with haematological malignancy, said blood cancers.

 

00:01:42 Will

And professor Walker.

 

00:01:44 Prof Walker

We have a lot of parallels. I trained and adult medicine and then I moved into paediatrics. Having done haematology as an adult specialist to look after the children with leukaemia and I was immediately committed then to developing skills further in the field of children’s cancer and worked a lot and leukaemia which took part in the dialogue that was taking place at that time about the development of clinical trials.

 

00:02:12 Music

 

00:02:17 Dr Halsey

It’s always been fascinated by the Bloods and also the way that Haematology combines a lot of time spent with patients and a lot of very intensive kind of clinical commitment, but also is very scientific and as a haematologist you actually use scientific tests in your everyday work in terms of diagnosing and treating children and adults with blood cancers, so is very attracted to working with children and their families, and I found that very rewarding and working on the commonest childhood blood cancer which is leukaemia?

 

00:02:51 Dr Halsey

And from that I can have moved towards really wanting to understand more about how to use research to improve treatment for childhood cancers.

 

00:03:00 Dr Halsey

I became fascinated by how leukaemia cells, which normally originate in the bone marrow, actually spreads around the body and can infiltrate the area around the brain.

 

00:03:12 Dr Halsey

They elect meninges, and I wanted to understand how leukaemia cells could live in such a different environment from the environment they normally find themselves in the bone marrow weather by understanding that we could actually identify ways of better treating leukaemia that spread to the brain.

 

00:03:28 Dr Halsey

And so I now have a research group working primarily on trying to understand more about leukaemia that spread to the brain and also trying to understand how we might improve the treatments we have for that all those are effective at preventing recurrence of brain.

 

00:03:42 Dr Halsey

Leukaemia actually can be associated with quite a lot of side effects for children both during their treatment as they grow up. So half my research group works in understanding how cells live in the brain and the other half on. How and why children get toxic effects of chemotherapy and how we might reduce those.

 

00:04:01 Prof Walker

100 opportunity to go in advance. My training in Australia at the Royal Children’s Hospital in Melbourne and was given the opportunity to work particularly in the field of brain tumours because no one else was doing it and having completed my training in Melbourne, I came back to the UK at looking for a consultant position and before I was appointed in Nottingham I ran a workshop saying, well, what is the scope of practise that we need to develop in the field at neurology and are invited.

 

00:04:31 Prof Walker

People from all over the country from different world to life and we fleshed out the programme that needed to be developed and then I ended up sharing the brain. Schumer committee in UK and we developed a series of subgroups that worked on the different brain tumours.

 

00:04:46 Prof Walker

We opened 13 trials in about 7 years and then went on to work with the European Branch Human Committee in C OP. All the way through, we were always exploring drug therapy. If you look at childhood cancer in general, a third of all cancers are leukaemia and they all potentially involve the brain. 25% of all cancers are primarily in the brain, which means that more than half of children with cancer have a brain component to their disease and therefore it’s successful therapy. And so this is a major problem for children’s cancer.

 

00:05:24 Prof Walker

If you look at it further back and look at brain cancer in all adults and children together, It’s estimated that something like 40% of all patients with cancer in both children and dulls. The brain is the rate limiting step to cure so if you don’t target the brain. Specially then you don’t control the disease. And so things like breast cancer. Lung cancer colon cancer, which happened very calmly in the adult population are high percentage of them can spread to the brain and if you haven’t treated the brain specially like that, we learned in childhood leukaemia disease will escape control in the brain.

 

And so therefore this is a really big talk.

 

00:06:04 Prof Walker

And I think a lot of the tumours occur do grow over the surface of the brain, where interest CSF therapy is probably the best design for delivering drugs to that part of the brain. When tumours grow within the body of the brain, then intra CSF therapy isn’t applicable. My experience of leukaemia was that if you put drugs into the blood stream it goes straight to the bone marrow.

 

00:06:29 Prof Walker

And it kills off the leukaemia cells very very effectively and your biggest risk as it kills off the rest of the bone marrow and you have to wait for that to recover before you can give him some more. But in the brain, it’s entirely different. You give the drugs into the blood stream, and most of it doesn’t get into the brain, and so therefore the effectiveness of your therapy is much, much reduced.

 

00:06:50 Prof Walker

In leukaemia we’ve all spent many hours delivering drugs into the spinal fluid to treat the tumour on the surface of the brain, but in brain tumours. It almost was never occuring.

 

00:07:02 Dr Halsey

The brain is very precious, if you like and very vulnerable to kind of toxins so the body has had a kind of barrier between the blood stream and the brain to stop things that might get into the blood stream.

 

00:07:12 Dr Halsey

Getting across to the brain and causing causing damage, and that’s what we called the blood brain barrier or love service. Spinal fluid barrier and these two barriers basically stop. Not just medicines but other toxins and impurities. If you like getting into the brain which might be very affected by that.

 

00:07:30 Prof Walker

Just struck me that if we really wanted to use drugs to treat brain tumours. We needed to think about how we got the drug into the brain better than we were doing it that to that date. Obviously, interests equal or interest CSF treatment to the leptomeninges was the one who was the greatest track record and leukaemia and that’s why I came to speak to Chris. We wrote this article about how we might approach the same problem in two different disease groups from different perspectives.

 

00:08:01 Music

 

00:08:06 Dr Halsey

People made the connexion that, as David mentioned earlier, that some drugs that get into the blood stream often don’t get into the brain, and so leukaemia cells, which are it is a blood borne cancer. So it circulates around the body and the leukaemia cells can get pretty much everywhere, so you can find the leukaemia cells in the liver and spleen and kidneys. And some people called the brain in particular what’s called a sanctuary site for leukaemia because the cells can kind of hideaway there and then not affected by the drugs that get into the blood stream that just over. Don’t get into the brain in the same way, so when they discovered that the leukaemia cells were hiding the sanctuary sites, they realised that they would need to try and kill the cells there as well as well as in the in the bone marrow and in the blood.

 

00:08:51 Dr Halsey

And the first approach that was used was radiotherapy, and so they used to use radiotherapy to the brain and the spine to kill off any leukaemia cells that were growing there.

 

00:09:02 Dr Halsey

The actually that that therapy was very effective. It reduced the incidence of CNS relapses. So relapses of leukaemia in the brain really significantly and caused a really huge jump in the survival of children with leukaemia. So with just the tablet based or the systemic chemotherapy about 10 to 20% of children were surviving and when they introduced this approach to give all children this radiotherapy then the cure rate jumped.

 

00:09:32 Dr Halsey

Very quickly within a couple of years of introducing this up to kind of 50-60% of children being cured. And so it looked like and it was established at that time that really treating cells in the brain leukaemia cells that might be hiding in the brain was essential to secure childhood acute lymphatic leukaemia. But one of the issues is we can’t actually see the cells in many children, so most of these children we were treating. If you like blind, we were JustGiving the radiotherapy because we knew if we didn’t that most children would really.

 

00:10:05 Dr Halsey

But it’s really quite hard for us to measure those cells. They don’t show up on brain scans, and we can take a little bit of the fluid from around the brain and look under the microscope, but that’s really quite a crude way of looking for leukaemia cells and probably misses most children who might have cells there at the door in that area, but aren’t necessarily free floating in the fluids.

 

00:10:27 Dr Halsey

And so they might be stuck to the surface of the brain, and so we don’t pick them up if we just take a teaspoon, save the fluid and have a look at that. We established that kind of paradigm if you like the old children with leukaemia need CNS directed therapy they need this therapy. This specifically gets around the problem of this of the drugs not getting into the brain, and initially we found that a solution to this was to use radiotherapy.

 

00:10:54 Prof Walker

I was really struck in that early work with the brain damage associated with CNS radiotherapy. I was really struck with trying to understand the nature of the brain injury.

 

00:11:05 Dr Halsey

However, although it’s very effective radiotherapy as David already alluded to, can cause quite a lot of damage to the child’s normal brain, particularly in children, of course, whose brain than their brain still developing their still making lots of neural Connections.  So if you shine radiotherapy that kills living cells, if you like onto the brain, it’s going to kill not just the leukaemia cells, but potentially some of the normal brain cells as well. And we found that children treated with radiotherapy, particularly younger children. The infants children under two were left with really quite significant learning difficulties after radiotherapy, and also even more in the way.

 

00:11:45 Dr Halsey

Shockingly, I think to us when these children grew up and 10 to 20 years after this therapy, a lot of them developed secondary brain tumours because of the damage that was done to the normal brain tissue. And so we cured these children of Leukaemia, but we’ve given them a longer term problem of the risk of developing a brain tumour, and it was up to 20% or one in five children who after this cranial radiotherapy as a young child due to their leukaemia ended up with a secondary brain tumours.

 

00:12:16 Dr Halsey

As some of those brain tumours were what we called benign brain tumours, gliomas, ET cetera and others were malignant brain tumours. But irrespective of whether it’s benign and malignant, both of them could cause problems to these children.

00:12:28 Dr Halsey

So this caused us to take a big cause. If you like what we were doing, we recognised that the treatment was essential to prevent the leukaemia coming back in the brain. But we realised that the radiotherapy was really not a good solution for the majority of these children. Peak Age of childhood leukemias aged between aged two and five. We hope to cure these children of leukaemia, so we’re hoping that they’re going to have 50,60, 70 maybe 80 years of life ahead of them. So we have to think very carefully, not just about how we kill the leukaemia but also any long term damage that we might be doing without treatment to their normal or the in particularly to the brain.

 

00:13:12 Dr Halsey

In the 70s and 80s, people realised that the brain radiotherapy was maybe not the optimal treatment and they started to switchover to using drugs to treat the leukaemia that’s hiding around the fluid in the fluid around the brain and they did this via a circumventing the blood brain barrier and the blood CSF barrier. By directly injecting the drugs into that fluid around them.

 

00:13:33 Dr Halsey

I said swapping over from the radiotherapy to the intrathecal therapy was done in stages. First, for what we thought with children at low risk of the of brain leukaemia coming back and then children who are at high risk overtime and it’s really only in about the last five to 10 years or so that we’ve been able in the UK to eliminate use of radiotherapy for all children with leukaemia and switch to this drug based therapy that we give via spinal injection usually and that we call intrathecal therapy.

 

00:14:02 Music

 

00:14:07 Prof Walker

Chris is illustrated very fluently. The story of the development of CNS or brain targeted therapy with drugs in the leukaemia challenge and it’s been a great success. They did three things really. They changed their dose of that. The selection of their steroid medicines, from Prednisolone to dexamethasone, which is much higher impact as the drug in the brain particularly. They increased the amount of interest. CSF therapy and also increased the doses of systemic chemotherapy, which would inevitably mean that higher doses of drugs got into the brain than previously and in order to do, although that the Haematologist had become really, really expert in keeping their children alive during this sort of very intensive therapy.

 

00:14:59 Prof Walker

I’m not to share that expertise in keeping them alive. Called supportive care across a whole community across the country coz it couldn’t be done in just one or two places. It had to be done wherever children with leukaemia being treated and so that was why it took probably a couple of decades to really intensified because you had to move gradually for people to learn the skills and adapt to the new therapy and then get the evidence to prove that it was working and I was observing all of that whilst I was trying to develop the brain.

 

00:15:33 Prof Walker

We tried intensifying systemic chemotherapy in brain tumours as a way of enhancing cure rates and giving them doses of drugs that made their bone marrow go away, so they had to re infuse bone marrow cells to make it grow back again. And sadly, it had almost no impact on the cure rates for brain tumours. With in tried using intensive chemotherapy including stem cell rescue, which is a mechanism for regrowing the bone marrow after administrative. Very very big doses of drugs and it hasn’t produced any beneficial effect in curing brain too. And so maximising systemic administration of chemotherapy wasn’t working, as a way of improving outcome and it took us about 15 years to realise that.

 

00:16:20 Prof Walker

The rule is one or two cases who did better than we expected, but when we came back to look at it, it was often coz they had a very good operation or something else had happened that made them survive and so that really made me so. Well, you’ve given the drugs into the blood stream isn’t going to be an effective way to intensify therapy. Why don’t we try exploring given drugs into the spinal fluid? Coz it worked in leukaemia and so that’s why we started to think about it. I’m principal investigator for an organisation called the Children’s Brain Drug Delivery Consortium and this is a charity funded consortium funded by children with cancer.

 

00:16:59 Prof Walker

Our aim is to raise awareness of the need to deliver drugs, specially to the brain to treat children’s brain tumours and one of our areas of interest is how can we develop interest CSF drug therapy? A lot of people who get brain tumours end up having a shunt put in, which is a drainage device put in to try and bypass the blockage and that changes the way the spinal fluid flows around the brain and also changes what happens to the drug. And so although you could say well will only do this and people without shunts.

 

00:17:33 Prof Walker

As about 25% of the children with brain tumours end up with a shunt that would exclude 25% of the patients for the benefit of this therapy. And So what we wrote about in the paper was to say that our experience is that if you change the route of administration into the CSF I, if you give the drugs into their back rather than into the brain, then you can still deliver the drugs into the spinal fluid if they have a shunt inside too and we don’t see in principle why that shouldn’t be.

 

00:18:02 Prof Walker

And that would get over the problem of sun making the patients ineligible. For intra Theatre therapy and but it needs to be studied in a trial, and so we need trials of this sort of technology to help us understand how best to do this safely and most effectively. And one of the trials we tried to design. In fact we did design that didn’t get launched was using the drug into the spinal fluid as an infusion rather than as a bolus could. You could then control the concentration of the drug over a prolonged period of time.

 

00:18:33 Prof Walker

Which may increase its effectiveness and control its toxicity. And that’s one of our proposals that we make in The paper. But progress is slow. Because they’re actually for licenced drugs for brain tumours in the world pharmacopoeias in adults and children. And so the drug therapy has not really been proven to be effective. Although we do use drugs which are unlicensed in children’s brain tumours, but their relatively ineffective. So despite 50 years of intensive research in adult and paediatric, your oncology only four drugs have ended up being licenced for use in brain gyms.

 

00:19:13 Music

 

00:19:17 Will

For a recent hands on experience of using the lessons of leukaemia to treat brain tumours, I spoke with Lissette Mayer from the Princess Maxima Centre for Paediatric Oncology in the Netherlands about her experience in treating modular blastoma in young children.

 

00:19:31 Dr Lisethe Meijer

Since a few years ago, I think we discovered that we do not know a lot about why a brain tumour growth. We And we have sent our brain tumour samples to specific laps and it was a lap in Heidelberg in Mornin tickets in Toronto where we have been looking at the brain tumour itself in much more detail to see if we can find vital brain tumour growth.

00:19:58 Dr Lisethe Meijer

And we’ve learned a lot about that, and the hope is in the future that we can be much more precise in giving the treatments to Stop the growth. There are hardly any brain tumours were just getting into my out is a good enough treatment because usually you can’t get the whole tumour out with Surgery, like when you’re elsewhere in the body. You always take a rim of healthy tissue around that Mark to make sure that that’s the small average rumour grows a little bit into the surrounding tissue, and to make sure that that is grown into the surrounding tissue, that you’ve also taking it out.

 

00:20:43 Dr Lisethe Meijer

But it’s a problem in the brain. You can’t do it there cause can take half a centimetre or a whole centimetre of surrounding healthy brain out, because then you severely damaged the patient, and therefore there’s always the chance of humour left where the surgeon didn’t see any tumor anymore, and therefore there’s almost always either chemotherapy or radiotherapy after surgery to make sure that your rate of the tumour once and for all.

 

00:21:15 Dr Lisethe Meijer

But the problem with systemic administered drugs is the blood brain barrier and the blood brain barrier is a very strong barrier to prevent. Toxins which are in the blood stream to enter the brain. And in large bulk tumour, that tumor itself produces blood vessels to grow, because everything that droughts needs oxygen. So if you give a pill or give chemotherapy by intravenous infusion and then it will get into the blood stream in the blood stream will get into the You will attack the tumour from inside.

 

00:21:53 Dr Lisethe Meijer

But because those blood vessels aren’t usually very good, the drugs can get over the blood brain barrier and the problem with leptomeningeal metastasis because it’s very thin layer of tissue. There’s no blood supply yet. You have to give drugs via intravenous injection or via built in a high enough though so it crosses the blood brain barrier. So comes from the body blood vessels into the CSF itself and then.

 

00:22:27 Dr Lisethe Meijer

Almost not possible, and then of course you get a lot of systemic toxicity which you do not want for the patient. Or you have to make a truck which is able to cross the blood brain barrier and can just enter the CSF. But the problem with that is that there’s not a lot of drugs which are able to cross the blood brain barrier because it’s so well, defence.

 

00:22:55 Dr Lisethe Meijer

In order to share can fence the blood brain barrier, you give interest CSF treatment. As Chris said, the test replaced radiotherapy. We are looking into brain tumour patients, an NBC in very young children where we rather not give radiotherapy because radiotherapy is an effective treatment. But the problem is you get a like they discussed in the leukaemia patients irradiate young brain. You get

toxicity, and that’s most of all cognitive impairments where you see if children are under five years of age or older, three years of age, and that if you irradiate the children, their quality of life diminishes significantly because they won’t be able to have schooling as they would have had had they not been irradiated, and especially radiating young children.

 

00:23:57 Dr Lisethe Meijer

They get much more problems when there in 2 adults H to be able to live on their own to be able to maintain healthy relationships due to their cognitive impairment. So, in young children with blastoma under the age of 3 to 5. We have now replaced radiotherapy with interesting as  treatment.

 

00:24:22 Dr Lisethe Meijer

Had sent you administered the drugs directly at the tumour site. You can significantly lower the dose which will be unable to generate systemic toxicity once it enters the blood stream. The drugs entered the leptomeningeal metastasis by diffusion, and therefore the contact between the drug and the two were should be long enough to be able for this process to take place.

With that being able to cure children without the need of radiation with keeping their survival as it had been previously with having a better cognitive outcome and therefore a much better quality of life for the child.

 

00:25:08 Prof Walker

Is you have to put an extra reservoir, but which is a small catheter that you stick into the head to deliver the drugs into the lateral ventricle and so that required an extra operation. And there were some complications are putting those reservoirs in. Someone got infected. They need taking out and replace. And when they tried to recommend this in the United States to be a trial that they could replicate, there was low enthusiasm to do it.

 

00:25:34 Prof Walker

So the process of administering intra CSF therapy, the technology involved wasn’t widely accepted by the medical community at that time, and it still is not routinely done. And one of the reasons we wrote the article was really to highlight that the evidence that intra CSF therapy may improve outcomes for brain tumours exists already Cos there are a number of trials where it was done in paper. The evidence is that it works, but in practise people are still very reluctant to do the extra operation put in a reservoir and to design trials with intra CSF therapy as part of the treatment programme because of the extra burden of risk for the child and family. And the uncertainty of the benefit.

 

00:26:23 Prof Walker

You know the interest CSF drug programme you have. Leukaemia is really quite burdensome isn’t here to minutes. I’d like to visit hospital anaesthetics, lumbar punctures.

 

00:26:29 Dr Halsey

Oh yeah, absolutely.

 

00:26:33 Prof Walker

You know, it involves the hospital in a huge amount of expense. There’s a big risk associated with the intrathecal drug delivery programmes. It really does occupy a lot of your time in your team, isn’t.

 

00:26:46 Dr Halsey

Uh huh.

 

00:26:46 Prof Walker

So the reason we wrote the article is to highlight that there was a potential benefit that there are technical difficulties. It would be really good if somebody could invent a better way of giving the drugs into the spinal fluid. In fact, I’ve had discussions with people who might be able to do that, but the technical development of such devices is complicated and involved. Big commercial and technical device development programmes which are not straight forward, but we are there for on the threshold of an error when using drugs. Directly into the brain may well start become more routine practise.

 

00:27:19 Music

 

00:27:25 Will

Have there been any indications of patients or any diseases that patients have that make them more suited to this?

 

00:27:34 Prof Walker

For the children who are very young who present the brain, Schumer, under the age of three or five years of age whose brain is still in very early stages of growth and development, they have already been subjected to the use of drugs into the spinal fluid because to try and delay the time when you might use radiotherapy to the brain to try and eradicate the remaining tumour for the reason that Chris outlined as being a problem. In the cameras, if you radiate young brains, they don’t work as well when you’re older either cuz your memory and your concentration span and your cognitive capacities are impaired and also you’re putting the child at risk of getting another brain tumours result of the radiation damage.

 

00:28:15 Prof Walker

So in the very young children we have been using intra CSF therapy. It’s never been subjected to randomised trials, so we’re doing it coz we think it’s the right thing to do, but we haven’t got very good evidence and that’s slightly inhibiting people. From making the leap because there isn’t that randomised trial evidence that everybody can see and say, we should definitely do this.

 

00:28:35 Dr Halsey

I mean within leukaemia we’ve now become a little bit of a victim of their own success because we’re so fortunate that now we can cure over 90% of children with leukaemia. That means it’s very hard to ask families to kind of take a leap of faith and trying new treatment if the current tree.

 

00:28:56 Dr Halsey

Hunt has a 90% cure rate and I think when children present with leukaemia I think in most families that you know it’s such a terrifying diagnosis that most families and patients themselves really focus completely on just curing the leukaemia and just getting rid of it and making sure that it doesn’t come back. And maybe secondary considerations like what will the treatment itself cause toxicity and side affects and things. The less important at the beginning, because they’re just so fixated on cure. If you like, and that’s completely understandable.

 

00:29:32 Dr Halsey

And that means that if you want to try and introduce new treatments that you think might be less toxic, but you’re not certain as to whether they going to be as effective as securing because you haven’t tested it. That’s a quite a difficult thing to do now, and you have to take that very slowly.

 

00:29:47 Prof Walker

The other thing which you mentioned Chris early on is that prioritising quality is survival. When getting consent from parents when they’re worried about their child dying from leukaemia is a problem in brain shimmers as well in that they have to often have a brain operation and the parents think the chances are there’s a very high chance of the child dying in the brain operate.

 

00:30:12 Prof Walker

And we can’t get them to consider research or trials which are seeking to reduce the long term damage to the brain at that moment, and it’s because they are so overwhelmed by this fear which is natural for parents of immediate loss of their child, and they can’t see that doing a trial and giving consent to trial which may impact upon how clever they are in the future, or how able they are to take part in society 20 years time. As being as important as trying to save their life at the moment.

 

00:30:49 Prof Walker

And that’s a real. It’s an ethical dilemma, actually. But we know it’s paediatricians and cancer specialists that actually the vast majority of the children were going to be cured. The leukaemia Acute Trials Committee has taken the cure rates from 50% to 80 or 90% in. In my professional life time, and so in terms of percentage chances of being alive then that’s really are given. There is a small chance at something disastrous might happen. So if you’re going to be alive for a long time I’m on the same stream branch imaginary blastoma. There’s an 80% chance of being alive in 10 years time. The number of children who die in the operator. I’m never known a child die in the operating Theatre in the last 40 years of my life unless they’ve come in acutely unwell and were dying before they got to the operating Theatre.

 

00:31:39 Prof Walker

But if they go into the operating Theatre in control. Then they don’t die. And So what you do in the operating Theatre that may affect their future long term. Intelligence is really important that you can’t get people to think I like as the parents are so scared. So I think there’s an overlap there’s something to be learnt there together is how do we communicate with families? We’ve got treatment. The big question for the treatment here is the quality of your child’s brain. In 20 years time and we want to do a study to try and make sure it’s as good as we can make, and it’s how we get that message across to worried people is actually a specific research problem. I don’t know what you think about that, could.

 

00:32:18 Dr Halsey

That is absolutely fascinating. David and I think you’ll be pleased to know that we are thinking about that very deeply in leukaemia now and I think that’s because we are in the fortunate position that worldwide we couldn’t cure 9095% of children with childhood. Yeah, and so we’ve recognised in our community that we can’t measure knew drugs about by whether they increase our survival rates.

 

00:32:42 Dr Halsey

What we’re looking for is whether they can produce the same level of cure but with better quality of life. And so we’re just literally in the middle of an international effort to reconfigure how we assess the success of our leukaemia treatments.

 

00:33:00 Music

 

00:33:06 Dr Halsey

The other reason we are victims of our own success is that we are because we cure 90% of children and leukemias. Fortunately, relatively rare, there’s actually not that many children where the leukaemia comes back and it comes back in the brain and things. So if you want to measure whether a new treatment is effective, need an awful lot of patience to get enough patients who actually have the leukaemia coming back in the brain.

 

00:33:27 Dr Halsey

To see whether your treat your new treatment is effective or not. So there’s two kinds of problems with that, which means that when we’re looking at testing new drugs and new approaches, we probably can’t go straight to the majority of children with leukaemia, and we probably need to focus on that. Children that don’t have other curative options, so the kind of areas that we might want to explore for testing new drugs would be children.

 

00:33:52 Dr Halsey

Whether leukaemia has come back where, maybe even the treatment that we have for recurrent leukaemia has failed and they’re left with essentially incurable leukaemia and at that point we can say you know it is this a time where we might be able to test one of these new drugs to see whether it makes any CNS leukaemia you have go away and see how long it can go away for.

00:34:11 Dr Halsey

We wouldn’t necessarily be able to promise a cure, but we would potentially be able to promise our mission. Those patients are aware there are only a few each year in the UK, so in order to run those kind of trials we need to team up either internationally and we’re very good at that and leukaemia of teaming up occur across different countries. So our next week in your trial, in fact, involves 14 countries across Western Europe to really to give us the opportunity to look at rare sub groups such as children with currency NS leukaemia but also possibly trained teaming up with a brain tumour community. So there’s no reason why if we’re testing, have safer new treatment is and how effective it is at getting good drug levels in the brain and things why we couldn’t have trials that included both children with CNS leukaemia, that’s come back in the brain and children with brain tumours. So that would be another very interesting way forward to explore.

 

00:35:05 Prof Walker

The model of leukaemia is really important coz leukaemia is a disease in the blood stream and it produces tumours that grow on the surface of brain. At Portman called the Leptomeningeal surface, and that probably gets there from the blood stream and Chris can talk about this coz that’s her research area and it gets from the blood stream onto the edge of the brain, into the meninges. And it can kind of grow specifically there and we see this pattern of growth in our malignant brain tumours now.

 

00:35:36 Prof Walker

Historically sold, the CIMA fell off the brain surface travelled round the CSF. And set up shop in the leptomeninges. But recent work suggests that she may be getting into the blood stream and going by the same route as we see with leukaemia. And that’s really important, because that means that the tumour cells are spreading the blood stream to get to the leptomeninges and brain tumours. That could be get doing that in brain tumours as well and underlines the proposal that Chris is just made that maybe we should be doing this jointly.

 

00:36:08 Dr Halsey

Yeah, from my point of view in terms of leukaemia and the kind of the current state of the art, if you like we have very effective therapies for CNS kimia. We show that you can cure leukaemia that spread to the brain by giving chemotherapy. What we don’t have is non toxic therapies and given our enormous cure rates for childhood bikini which is a great thing to be celebrated, we do need to think very carefully about whether we can achieve the same cure rates with kinder and gentler therapies.

 

00:36:41 Dr Halsey

If you like and I think that’s a really important focus for us and we mustn’t be complacent by just saying we’re curing the Kenya, we have to think about the quality of the treatment they were giving. And new drug discovery of less toxic drugs that we can give effectively to the brain with really, really important in the childhood leukaemia field and it’s difficult to get enough pharma company interest in that if you like because of it. Because of such outcomes are rare and relapsed brain leukaemia is even rarer, but I think we just need to keep emphasising how important it is that we get really effective drugs that are non toxic in this area. And I think one of the key.

 

00:37:21 Dr Halsey

Steps that will allow us to realise that in chartered leukaemia is actually being able to measure the leukaemia in the brain. I think because we can’t see it were treating these children blinds. It’s very difficult then to bring in a new therapy and say is it better than the current therapy? Whereas if we were actually able to have what we call biomarkers, so things that we can measure that tell us how much brain leukaemia there is and how clearly it’s responding to treatment and whether there’s early signs of it growing back again. Then I think we’re in a completely different research space where we can start comparing our current treatment. That’s relatively effective, very toxic against treatments where we know that we hope they’re going to be much less toxic, but we’re not quite so sure about whether they’re going to clear the brain. Leukaemia is effective.

 

00:38:07 Dr Halsey

So that would really revolutionise how we treat brain leukaemia and that’s something that we’re exploring in the next childhood beginning trial as an adult scientific study which is being led from us in Glasgow but has collaboration across 14 different countries to collect samples of the cerebrospinal fluid and to measure for sub microscopic amounts of leukaemia in that fluid by a variety of different techniques. And see if we can use the results of those measurements to predict which children will have the leukaemia recur In the central nervous system and so I’m really hopeful then the next 5 to 10 years we will have the tools that we need To enable us to test really much more innovative drugs that can cure both leukaemia and brain tumours, potentially without the current toxicity we see with our current treatments.

 

00:38:55 Prof Walker

I think what Chris is just said about being able to measure CNS involvement using a variety of scientific techniques is really, really important for the brain tumour agenda. And I think we should join forces on that because a lot of the techniques are specific to the particular leukaemia. But some of the techniques about detecting very small signals and I think we could learn from the leukaemia trials community for about that.

 

00:39:22 Music

 

00:39:27 Prof Walker

The device we’ve worked with for giving drugs directly into the brain tissue itself, called the Renishaw infusion device, has got a skull mounted airport that comes out through the skin, and it’s been proposed that that could be modified to be an interest equal to nice and it can be put in and taken out and the catheter could be placed anywhere in the spinal fluid you wished and if we introduce that even with the device development, you need to do to make it that would revolutionise leukaemia care, because suddenly they wouldn’t need to be put to sleep.

 

00:39:59 Prof Walker

It’s because the port comes out through the skin. You attach a syringe directly to it. You clean it and to sterilise it And we’ve been using it and children and leaving them in. And then you can take them out again at the end of the therapy and you wouldn’t need to put him to sleep every time. Could you imagine how that would change your clinic?

 

00:40:17 Dr Halsey

I mean, it would be amazing. Amazing.

 

00:40:20 Prof Walker

And it’s those sorts that So what we’ve concluded in the drug delivery. Consortium is that the practise in this area of delivering drugs. The brain will be will be driven by device development that if we could get a device that creates an easy way of delivering drugs to spinal fluid that will accelerate it. Coz what’s holding it back is the device is a clumsy, risky thing to use, and the alternative is put people to sleep and stick a needle in their back. Is a painful procedure that you need to and the children worry about it.

 

00:40:56 Prof Walker

And so I think the agenda here will be driven by Wolf pig be accelerated if devices can be developed that overcome the deficiencies of the current method of Drug Administration to spinal fluid. Because although we’re used to them, they are actually extremely burdensome. And I remember when the we went from 6 lumbar punctures to 10 or 12 lumbar puncture. The health economic discussions in the hospitals as to how we’re going to manage that in or the leukaemia units around the country. It meant and where they had one anaesthetic list. A week, they needed 2 or 3 and the costs of all that were really difficult to find.

 

00:41:34 Dr Halsey

And I mean we have up to 26 lumbar punctures on some of our protocols. Plus we’ve published recently that you know, and in fact, service, St Judes, that general anaesthetics have an effect on your cognitive repeated general anaesthetics, in particular use of nitrous oxide during anaesthesia, in Association with methotrexate, is associated with adverse neurocognitive outcomes as well. So if you can do things without anaesthesia, make a massive difference we reviewed all the drugs in pharmacopeia  for their suitability for giving drugs into the spinal fluid, and we concluded that we wouldn’t give me the traffic to anybody.

 

00:42:12 Will

That was quite the conclusion. But as well as learning from leukaemia in brain tumours and from brain care in leukaemia has there been any lessons learned or do you think there is room to reach out to other disease areas be they developing treatments like your Advances in Immuno therapies targeted molecules or combination therapies or other parts of the healthcare industry mentioned the device design and implementation there. If more people are involved, is that many hands making light work or too many cooks in the kitchen?

 

00:42:48 Prof Walker

Yes. Opportunities people grasping upon the right person coming to the fore who’s got good idea and then getting through the commercial process. The commercial process is extremely complicated and there can be no guarantee that your good idea will get developed that’s my mission.

And luck that is a big part of it.

 

00:43:07 Dr Halsey

But I think in answer question will yes, possibly. I mean, you know there’s I’ve always been fascinated by the fact that leukaemia cells love living in the Leptomeninges and David mentioned that you see that a solid tumours also get very attracted to left and injuries. But Interestingly, in multiple sclerosis lymphocytes which are obviously the non malignant counterpart of leukaemia living in the leptomeninges two and set up little homes within them. Leptomeninges and produce antibody and that that production we know in multiple sclerosis can be stable over many many years and so you can imagine that areas where we understand the biology of how cells can survive in what is normally in an area which as he doesn’t have normal cells in it, it’s normally what we call in a secular fluid. Might have translations into other areas.

 

00:43:56 Dr Halsey

And I’ve always had the hope that some of our work might have an overlap with multiple sclerosis, which is such a hideous disease. And you know, with lack of really effective treatments, so you know, I think you always need to be alive to these possibilities that there may be synergies with quite distant specialties, but some.

 

00:44:13 Prof Walker

I think the other thing what you’re talking bout. There is the fact that the microenvironment of the brain. And is infinitely variable. And what happens in one part of the brain doesn’t apply to another part of the leptomeninges isn’t micro environment that has unique qualities, just like the thalamus is a different micro environment to the cortex or to the cerebellum, and the brain is not a single organ, it’s many, many organs genetically controlled with completely different mechanisms to on one part of the brain compared to the other.

 

00:44:45 Prof Walker

And I think the leptomeninges, the covering of the brain. They have their own environment is not a brain, is actually the coverings and it’s the vascular space at the junction between the CSF spaces, the fibrous material that contains the CSF that has this particular quality. And so, thinking about how you can manipulate the micro environment to influence the equipment strategy.

 

00:45:10 Dr Halsey

Absolutely.

 

 

00:45:16 Will

Is there a useful hub of information that they could get in touch with you through? Or are there hubs for local trials and the clinical centres? Any patient advocacy, any patient support, groups, anything that you’d like to plug now for them?

 

00:45:28 Dr Halsey

For leukaemia, yes we have a lot of support for parents and their families in ways that they can access Information about research that’s going on. So probably one of the best sources of information is there. The CLG website so the children’s cancer and leukaemia Agree at professional organisation run for all healthcare professionals looking after children with leukaemia and cancer but also having excellent parent resources and support A lot of research into this area, so there are very good source of information. I’m sure David has a lot to plug for brain tumours. Listen very good patient support groups there.

 

00:46:04 Prof Walker

Yeah, so the drug delivery consortium is a collection of Specialists interested in developing research for drug delivery their interest. They have patient involvement. We have representations from research councils and funding bodies who listen to what we’re saying and we’re getting our message across in a progressive way in this podcast is part of that process. Sharing this debate in the broader community from different perspectives is a kind of an important academic process.

 

00:46:36 Dr Halsey

Totally, I’m buzzing with ideas and David I’ll email you after.

 

00:46:43 Dr Halsey

Probably not for recording in this thing, but yes, I think there’s so much that we can do together and I think we do tend to sit a little bit in ivory towers. You know, working with our known close called colleagues and you know it’s a recurrent thing in science, isn’t it?

 

00:46:56 Dr Halsey

You really make the breakthroughs when you cross boundaries across disciplines and bring people together who have very different perspectives on the same problem. If you like so I think this is really been fascinating.

 

00:47:07 Prof Walker

Which one is set for drug delivery group with the IPCC and you’ve just convinced me that we should be including the haematologist?

 

00:47:14 Dr Halsey

Yep, definitely.

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