With the work showing that we’ve made progress, we’ve improved the median survival for malignant gliomas significantly over the last decade, we now have a very extensive pipeline of new treatments and new approaches and new delivery methods that are being evaluated in clinical trials. With that and with the fact that we have seen progress although it’s not enough, that we have seen progress with this approach I’m very optimistic that with some of the newer approaches that we’ll see even more success.
Are there particular brain tumours that have benefitted from improved drug delivery systems?
Our work with using interstitial chemotherapy, with using polymers that release chemotherapy, has been focussed primarily on malignant gliomas in adults.
And why is that?
That’s the patient population that there’s really no effective therapy; the median survival was 9 months, no matter what was done, when we started. Now the median survival with local delivery plus systemic chemotherapy, Temodar, plus radiation therapy and plus the advances in surgery and intensive care is now more than 20 months. Whereas before it was rare to see a long-term survivor now it’s common and 20-25% are living several years after diagnosis. So we’re seeing a different outcome which is encouraging because it really is a change in the outcome for this terrible disease but it’s still very unsatisfying in that it’s still a terrible disease and it’s a terrible outcome, we could do much better. Nonetheless, the fact that we’ve made progress means that we should focus on children now and bring these advances to children, which is a harder population to treat, and we should use much better both drug delivery systems that are being developed and much better therapies.
What are some of the challenges that have been faced and how have these been overcome?
When we first started the concern was could you put very high concentrations of drugs directly in the brain, there was concern that it might be toxic. These are very strong drugs that have toxicity so the question was was it safe to do this and also was there a mechanism that you could even do this with. So Bob Langer, who is professor at MIT, developed a biodegradable polymer that in fact he showed was safe and could release in a controlled manner over several weeks instead of over minutes, the way we currently give drugs intravenously. Then we showed that it was safe in the brains of first small rodents and then higher animals and then in 1987 we began studying it in people in a dose escalation study and showed that in fact it was safe in people. Then the criticism was, well, it works in animals and it’s safe but is it really effective in people? Will it be effective? Anybody can cure cancer in mice but would it really make a difference to people? So what we elected to do and was very unusual at that time is we used the same rigour that we used in the laboratory of doing carefully controlled studies, we did it with people and we did a randomised prospective placebo-controlled study. We put polymers with no drug and polymers with drug and otherwise best available therapy first in 222 patients who had failed all other therapies, end-stage adult malignant gliomas. We showed with that that in fact there was a 50% improvement in survival with that one variable of having the polymer with the drug in it. On the basis of that we expanded to using it as initial therapy with studies here in Europe as well as other studies in the United States.
How do the findings from preclinical studies relate to the clinical situation?
We modelled out that there was a benefit, that it was safe and effective, and we did all the pharmacokinetics in animals, first in vitro and then in animals. We really were very confident that at least experimentally we could show a strong benefit. Then the question became could we design clinical studies to truly parallel what we had learned in the laboratory and to see whether the benefit translated to people. We are very pleased with that, that in fact the survival curves are almost superimposable, that you see the same percentage of improvement in survival and improvement in long-term survival in the experimental models as we subsequently saw with people in phase III studies.
Why is improved drug delivery particularly important for the treatment of paediatric brain tumours?
The brain has a way of protecting itself, it’s called the blood-brain barrier. It’s put there by nature so that things that could harm the brain, toxic substances that might be in the environment, don’t get into the brain, it’s a very protected site. So a lot of the therapies that we do to harm the cancer could be harmful to the brain and so the brain has this wonderful mechanism for blocking our therapeutic agents from getting into the brain. So drug delivery systems are very important because they allow us to bypass the natural defence of the brain against drugs or other therapies, immunotherapies, biological therapies, that we need to get into the brain so that they can reach their target site.
What does the future hold?
We now have more effective agents. We have biological agents that have never been tried before. We have a tremendous knowledge of the molecular genetics of childhood cancers and adult cancers that allow us to target specific overexpressed genes that we might be able to then benefit those patients with those very targeted therapies. We do have multiple methods of delivering therapies directly into the brain. We have polymers, we have all sorts of additional polymers other than the FDA approved Gliadel polymer. We have microchips where we can place multiple drugs simultaneously into the brain and then release them in a controlled fashion externally. That’s at a very early stage of development but we’re working on that and we’ve done that successfully in the laboratory. And there’s convection enhanced delivery and methods of infusing under pressure drugs to get them into the brain and also methods of disrupting the blood-brain barrier so that you open up that barrier, deliver the drug that’s necessary and then close the barrier again. So scientifically we’ve advanced significantly and now it’s a question of developing the clinical trials to make that beneficial for patients.
Why are workshops like this important?
These workshops are important because they cross-fertilise across age groups. The tumours that children get are special, they are similar biologically. The brains pose all sorts of different problems, the developing brain in some ways is more resilient than an adult brain, in some ways it’s much more exquisitely sensitive to damage because the development is so critical. So every age of the child brain tumour poses a different set of advantages and disadvantages that need to be taken into account. But I think the major thing is that we sit down and we talk and hear what’s been successful and what’s not been successful and we cross disciplines and learn how to do things better. It’s a huge advantage.
What is your take-home message?
We’ll say that it’s not only the pivotal papers and studies that showed the benefit of using these chemotherapy wafers but now there have been meta-analyses involving over 6,000 patients that have been in trials with chemotherapy wafers. If you do a meta-analysis the overall survival is significantly improved over standard therapies. I think that leads to a very strong argument that this should be added routinely to the armamentarium in combination with systemic chemotherapy to help adult patients with malignant gliomas. It behoves us to extrapolate that to children and safely be sure that we can do similar approaches for these very devastating diseases.
