Childhood cancer survival-rate increases threatened

New drugs
If we don’t address the problem now, the rate of introduction of new drugs and treatment approaches in children with cancer will be slowed down. Children will carry on having old-fashioned treatments which, although they are effective, are nasty to have and can be quite toxic in the long-term.
Professor Kathy Pritchard-Jones
Despite progress made in the developed world, especially in the last 50 years, cancer remains the leading cause of death from disease in children between the ages of one and 15 years. If we are to continue to improve the survival rate from childhood cancer, to reduce the toxicity of treatments and to mitigate their long-term side effects, data sharing and increased international cooperation in clinical studies as well as strong partnerships between all concerned groups will be necessary, according to researchers.

In a series of articles on childhood cancer published in The Lancet Oncology, Professor Kathy Pritchard-Jones from the Institute of Child Health at University College London (UCL), and authors from other institutions across the world, including Professor Richard Sullivan, from King's College London and King's Health Partners Integrated Cancer Centre, have warned that steps should be taken to ensure improvements to cancer care for children continue.

Professor Pritchard-Jones spoke to at length about the need to protect and promote innovation in cancer treatment, and why the general consensus has come to be that children with cancer treated on clinical trials tend to have better outcomes…

How obvious is the threat to improved cancer survival rates in children? Has the EU Clinical Trials Directive already had a discernible effect on the rate at which new drugs are emerging?
It’s fairly obvious that in the Western world a plateau of sorts has been reached due to a combination of factors. There is only so much to be achieved with ‘blunderbuss’ chemotherapy, radiotherapy and surgery, and we have reached the point where eight out of 10 children can be cured by those methods. Through clinical trials, the rate of progress has been steady at about one per cent per annum for the last 50 years; that is, from 30 per cent to 80 per cent survival rates in half a century.

However, the rate of progress has definitely slowed, partly because there’s not much more that we can get out of the treatments available now, but also because new drugs are needed. New treatments for cancer have to be trialled in children who have unfortunately relapsed or not responded to treatment and there are very small numbers of those patients, so meaningful studies must be carried out on an international scale. As well as requiring a lot of time, money and effort, clinical researchers need access to the drugs from pharmaceutical companies to carry out trials.

The only thing that is behind the rate of improvement in survival rates until now is that it has always been possible to put a child newly diagnosed with cancer into some form of clinical trial or study. This constant progress was partly because there was a very wide portfolio of studies open for all diagnostic groups. Now, because the process is getting more expensive, trials are only available to perhaps half of children, while the rest continue to receive standard care. Standard care is fine, of course, but it’s not going to make things better for a child diagnosed with the same condition in five years time.

How do factors other than strict and complex regulation compound the problem?
Clinical trials on childhood cancers are not a high priority for the pharmaceutical industry, because the numbers of people affected are small and it is not seen as a big market. At the moment we tend to ride on the coat-tails of drugs that are successful in adults. While we have the wherewithal to do the studies, more money is needed.

One example is the drug Imatinib, which was the first ‘magic bullet’ to transform the care of adults with chronic myeloid leukaemia. Ten years later, it has been through trials in children who have a different form of leukaemia but the same target. It’s starting to show real benefits in making that treatment safer and more effective for children. That’s the sort of model that we’d like to follow, but it has only worked because the drug was already successful in treating adult cancer, it was on the market, and the company wanted to do studies in children.

There is an incentive in the regulatory system to encourage drug companies to do paediatric studies as a way of encouraging innovation in children’s treatment, but the incentive – a six month extension on their patent – is too small. It is very difficult for academic investigators, who begin designing a clinical trial and obtaining all the necessary approvals, when a drug company decides not to take the drug concerned to market and access to it is suddenly lost.

We will only make progress this century if we have a new way of working with the regulators and the pharmaceutical industry. They have hundreds of drugs, designed to hit specific molecular and biological targets, and some of those will definitely have some benefits in children’s cancers. The challenge is that there aren’t many patients available to test new treatments on because the current treatments work in most cases.

The increased cost of carrying out clinical trials is also off-putting. I published a paper several years ago, when I was president of the European Society of Paediatric Oncology (SIOPE) in which we surveyed all of the countries in Europe. It showed that the introduction of the Clinical Trials Directive in 2004 had led to a tripling in the cost of doing clinical trials, without any noticeable improvement in safety for children.

Professor Sir Peter Lachmann appeared on Radio 4’s Today programme last week and suggested Phase III clinical trials should be removed. Do you think such a move would be beneficial?
I think I would agree with him there. A Phase III trial is really all about optimising what is already known to work reasonably well, certainly where children’s cancers are concerned. The problem is that cancer treatment is toxic by its very nature; it damages cancerous cells, and it damages normal cells. During a clinical trial, all those side effects have to be reported to the regulatory authorities, even though the researcher knows they’re going to happen because they’re administering these nasty treatments.

It would be a different story if they were based on risk assessments, of course, as there will be Phase III trials where you’re trying to put a brand new drug in combination with the standard treatment. In those cases it is necessary to be very vigilant as there might be, for example, new toxicities that were not anticipated.

What we’re asking for in terms of regulation is that the amount of scrutiny, regulatory approval, insurance, indemnity and so on needed for a clinical trial is adapted to reflect the risk to the patient of being in that trial as opposed to the risk of receiving the standard treatment.

What kind of approach is needed to encourage the development of new drugs and treatments for childhood cancers?
At the moment, companies ask the regulatory authority for a license to use a drug in humans. The authority can pass a waiver which means paediatric studies don’t have take place if the aim is to use the drug to treat lung cancer or Alzheimer’s or another condition that is not likely to affect children. But the molecular target the drug has been made to reach might be one of the drivers of a childhood cancer. Sometimes drug companies need to work with biologists who understand the molecular drivers of childhood cancer, so if a drug looks theoretically good, academic researchers can be given early access to it.

On the other hand, when the regulator tells a pharmaceutical company that they will not receive a marketing authorisation unless paediatric trials are conducted, the company then has to seek permission for those studies and find participants. The conversation between the regulators and the pharmaceutical industry needs to have the involvement of clinical trial groups and the parents of the patients themselves at that early stage, so that when a clinical trial is suggested, it is a logical step. The patients who need a new treatment enlist, and the clinical research scientists who treat those children under standard protocols are already working together in a network. That way, when a new drug comes along that looks promising, they know how to do the trial in that group of patients and can do it quickly and efficiently. The children then get the benefits more quickly too.

What could be the long-term consequences of failing to address this problem?
If we don’t address the problem now, the rate of introduction of new drugs and treatment approaches in children with cancer will be slowed down. Children will carry on having old-fashioned treatments which, although they are effective, are nasty to have and can be quite toxic in the long-term. Unless we carry on trying to bring new treatments into childhood cancer therapy, then we’ll stagnate and stop improving.



Are there any sustainable and environmentally sound alternatives to mitigate this man-made environmental crisis that you mention? I guess it is not only retreat, right?

Commented Christian Appendini on
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