Revisiting intrathecal therapy for childhood medulloblastoma

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Published: 8 Feb 2016
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Prof David Walker - University of Nottingham, Nottingham, UK

Prof Walker 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 the use of intrathecal therapy in children with medulloblastoma.

In particular he discusses the findings of a literature review looking at the range of drugs that may be suitable for intrathecal administration.

The analysis found 126 candidate drugs of which only 12 were selected as eligible for further clinical investigation at this point. A further 15 were thought probably for further pre-clinical investigation.

Childhood cancers affect about 1 in 600 children and about a quarter of them arise in the brain. Medulloblastoma is the second commonest brain tumour and the commonest malignant brain tumour in children so it’s really quite a significant problem. In the UK that means about 80-90 new cases are diagnosed a year, however, so that’s not huge numbers.

What are the challenges in treating children with medulloblastoma generally?

It can present at any time from shortly after birth right the way through to adolescence so the main challenge is making a diagnosis. Often it’s difficult to make a diagnosis because the symptoms are indistinct and there are often delays and the families become upset about it. When they first come to hospital they may have raised pressure in the head and that can threaten their life immediately so they often need urgent or even emergency surgery to decompress their raised pressure in the head, so that’s a big challenge. Then you have to make the diagnosis which currently means that we need to do a biopsy or an operation to remove the tumour and that’s a big challenge. Then once you’ve got the diagnosis you have to decide what would be the best way of trying to treat the tumour so it never comes back again. That’s where some of the complexity creeps in.

Medulloblastoma has now been categorised into four subtypes, the treatment we use is a combination of chemotherapy and radiotherapy. When we use radiotherapy to the brain in very young children, under the age of 3-5, it damages their brains in a way that limits their subsequent development and intelligence. So we don’t like using radiotherapy in children under 3-5 because we’re worried about that brain damage. So for the under 5 year olds we use mainly chemotherapy and use the radiotherapy in a controlled way in limited areas to boost the effects of the chemotherapy. In older children the evidence is that we can use radiotherapy more safely but it still does cause some damage to the brain and because we have to treat the whole of the brain and spine it also can damage the spine such that it doesn’t grow.

So what we’ve been discussing today has been about how we could enhance the effectiveness of chemotherapy so that we may in the future be able to limit the amount of radiotherapy we give to everybody because of this effect of damaging the brain and the spinal growth.

How could intrathecal therapy be of benefit in this clinical situation?

When you give chemotherapy intravenously it has a lot of side effects and the side effects you get are largely because the bone marrow is turned off by the chemotherapy and it stops working for a week or two and the blood counts fall and then they’re at risk of infections. They get nausea and vomiting and they become immunosuppressed. If you give drugs directly into the brain, into the spinal fluid, you only have to use about one two-hundredth or one three-hundredth of the dose and so all those systemic side effects would be abolished. But if we give it into the spinal fluid it only treats the surface of the brain so it wouldn’t treat the tumour cavity or the tumour itself, it would treat the surface of the brain. But that would be quite helpful if that was proven to be really effective because that may mean we could avoid using the extended radiation fields that damage their growth and also damages the bone marrow actually.

What drugs could be delivered via this route?

What I was talking about in this session was a systematic literature review that we did to try and identify suitable chemotherapy drugs for administration into the spinal fluid. Because we’re planning to administer them directly into the spinal fluid they don’t have to get across the blood-brain barrier because we’re putting a needle into the spinal fluid across the blood-brain barrier to put the drugs directly in there. We thought that that would give us a new list of drugs to use and test because they would need different chemical properties if we’d got them into the brain by putting a needle through the blood brain barrier. Because a lot of the drugs we’ve used in brain tumours to date have other physical properties that help them get across the blood brain barrier and the common one is how soluble they are in fats, that’s called lipid solubility. Drugs that are very soluble in fats get into the brain more easily; an example would be anti-epileptic drugs. So if you have epilepsy the drugs that treat epilepsy are mainly very lipid soluble because they can get into the brain and suppress the electrical impulses.

If you give drugs directly into the spinal fluid you can use entirely different drugs that aren’t lipid soluble because you don’t have to cross the blood-brain barrier. So our research looked at 119 drugs and found that there wasn’t enough information in the public arena for us to know if they’re suitable or not. So that raises an important issue about availability of scientific information from the drug development systems and that was quite frustrating. But of the rest we identified a list of twelve drugs that some of them aren’t in regular use but could be suitably harnessed given by this route which could bring them up and make them more useful and repurpose them for this route of administration.

Can you tell us more about the drugs identified that may be given intrathecally?

The top one that came out was etoposide, the second one was carboplatin. We rejected the drug that’s used most routinely in intrathecal use for leukaemia which is methotrexate because our search of the literature found that it was very toxic and we wouldn’t recommend that as a drug to be used and we don’t generally use it. There are other drugs – topotecan, fluoxetine – so a variety of different drugs; I can’t remember all eleven spontaneously.

What was the main conclusion of the intrathecal drug analysis?

The main conclusion was that there are several drugs that could be tested by the intrathecal use. There has been some preliminary experience with them and we’re trying to promote a programme of doing this more frequently because we feel that administering drugs into the spinal fluid is safe, it’s feasible, it’s less toxic and it could well be a very new avenue of development in this group of diseases that could have big impact. Although we have studied it in the literature mainly in medulloblastoma, that’s because it’s the commonest tumour and therefore is going to give us the most information. There are several other children’s tumours that spread to the spinal fluid down the surface of the brain and these drugs would be worth exploring in those diseases too.

What further research is needed?

The first step is to get everybody tuned up to giving drugs intrathecally for children with brain tumours. There are a number of technical things to do with surgery about putting devices in to allow to permit drugs which are routine things to do. But what you want to do is develop an increasing consensus on the standards of practice so that this becomes a routine thing for all the centres to do equally. Then one of the suggestions that came out of the workshop was we survey all the centres and say how many are actually using this method of administration for brain tumours, how common is it, what are their main problems, what protocols do they follow? Then probably we would hold a consensus meeting in the near future where we discuss those things and start to collect information about the safety and efficacy of that sort of treatment. Then the final thing would be to introduce it into more trials of new therapy.

Can you comment more on the safety of intrathecal administration in children?

Children tolerate treatment for cancer actually rather better than adults do; they’re very resilient, their families are very supportive. If there’s a strong technical argument most families agree to doing these things. To give drugs safely into the spinal fluid you need to have a device placed into the brain or the spinal column that allows you to administer a drug to that route. That’s a device that goes under the skin and we access it with a needle that goes through the skin. We insert it into the skin in such a way that the nerves are cut to the surface of the skin and so it’s numbed permanently so it isn’t a painful procedure to have the needle put in. Then we can administer the drugs directly into the spinal fluid. It’s associated with almost no symptoms, the children tolerate it. Once they are familiar with what you’re doing they tolerate it very well by and large. Of course some children don’t tolerate anything and we can’t always turn them into perfect patients but they often learn by a variety of psychological techniques to tolerate these sorts of procedures.

Then when we can give the drugs regularly into the spinal fluid then we’re in a position to see how effective they are and it’s very well tolerated, it doesn’t have all these side effects of the big doses of the same drugs given by mouth or intravenously.

Are clinical trials underway yet?

Yes, in children under the age of 5 who present with brain tumours there’s one group of patients who have a condition called AT/RT, or atypical teratoid rhabdoid tumour, which is a bit of a mouthful. They are routinely recommended to get intrathecal therapy and children who have brain tumours under the age of 3 with medulloblastoma, they are recommended in many centres to have intrathecal therapy. So it’s not new but it’s not widely used. We think that there is a great opportunity to extend its use to more problems with brain tumours because of its fantastic ratio of effectiveness over toxicity. We would like all our treatments to be less toxic.

What is your take-home message?

One of the very good things about this conference is it brought people together from different centres who have all had significant experience. We all seem to agree that this is a good priority to take things forward, so it’s not just one person’s view, it’s actually three major centres. There are several surgeons here who think technically that the procedure is something that they would support, it would be in the interests of the patients. So I think this is the beginning of a growing consensus and will lead to practice change.