Child cancer survival: an interview with Prof Kathy Pritchard-Jones …

Posted on Sep 1st, 2013

From http://www.news-medical.net/news/20130724/Child-cancer-survival-an-interview-with-Prof-Kathy-Pritchard-Jones-University-College-London.aspx

Please can you give a brief history of childhood cancer survival rates over the past 50 years?

Back in the early 1960s, just before chemotherapy really started to be used, only about 30% of children survived cancer. That was mainly because they had cancers that were amenable to surgery.

So, with the growth of chemotherapy and the understanding of how to use it, we’ve seen a steady improvement from 30% survival rates back in the 1960s to around 80% of children expected to survive childhood cancer in the 2000s.

What factors do you think were largely responsible for this remarkable improvement in survival from childhood cancer?

Probably the most important advance was, of course, the availability of chemotherapy – that started to be used in the 1960s. However, for this to have a big impact at the population level, it needed to be rolled out systematically and safely . This required doctors to take an interest and specialise and pull together the resources they needed to treat children in this complex area.

Treatment of leukaemia was the first childhood cancer to show rapid improvements in survival – from a starting point of 10% in the early 1960s to over 60% by the 1980s. This was probably because haematologists were able to introduce innovations in diagnosis and treatment through their own efforts and had very effective chemotherapy to use, whereas treatment of solid tumors required coordination of a much larger number of disciplines, including imaging, surgery and radiotherapy, that all had to develop expertise in rare tumours that did not form a large part of their regular clinical practice.

Also, many chemotherapy regimens were less successful in achieving complete or very good partial remission and the standard approach to ‘local control’ of a solid tumour that was used in adults (wide exision and/or radiation) carried the risk of unacceptable side effects in the growing child.

Ultimately, professionals specializing and working together to develop the whole team’s expertise in these rare diseases at a national then international level has enabled well-designed clinical trials to be conducted in a stepwise fashion. This, together with a high rate of participation of newly diagnosed children with cancer in these trials, has led to a continuously improving clinical research environment based on strong partnership working.

How many children still lose their lives to cancer each year?

In high income countries, where treatments are the most effective, just over 5,000 children still die each year from cancer before their 15th birthday. By contrast, over 95,000 children die each year from cancer in low and middle income countries, which are home to ~80% of the world’s children.

Do you think the progress in childhood cancer survival rates is currently threatened?

Undoubtedly yes and for a complex set of reasons. First, in high income countries, the rate of improvement in survival and mortality has really slowed down since the year 2000. (Pritchard-Jones, K., Pieters, R. et al. (2013) Sustaining innovation and improvement in the treatment of childhood cancer: lessons from high-income countries. The Lancet Oncology. Volume 14, Issue 3, Pages e95 – e103)

The only way we’re going to continue to make progress here is through introducing completely new treatments that are more effective than the intensive chemotherapy we use currently. This means harnessing the explosion of new, more targeted anti-cancer drugs, largely developed for adult cancers, and using them intelligently to treat children’s cancers through a biology-driven approach.

Many of the same molecular pathways are involved, although the mechanism of target disruption may be different, so direct extrapolation from the adult experience is unlikely to be possible.

Paediatric-specific trials with appropriate companion biomarker analysis will be crucial and most will require international co-operation to reach their recruitment targets. However, such trials are becoming increasingly expensive and bureaucratic to conduct, especially in the paediatric age group and across national boundaries.

There is also a need for more support for preclinical research in childhood cancers, so that the molecular drivers are better understood to allow appropriate priorisation of the plethora of targeted agents for early phase clinical trials. The availability of funding for such research in rare diseases is therefore a further threat.

Second, for the 80% of children that live in the parts of the world with fewer resources, the challenge lies in getting governments to prioritize and include children in their cancer plans and to develop an infrastructure to deliver at least the basic treatments safely and as effectively as possible.

Twinning programmes with institutions in high income countries have supported initiatives that have allowed local teams to start to treat those cancers with the highest cure rates. This has brought benefits not only to the children with cancer but also to the general child health services locally, through staff training, new equipment and the motivation that comes from successful treatment of what had previously been a hopeless or difficult situation.

Supporting the use of evidence-based decision making through involvement in clinical trials and studies is very important, yet many countries still do not even have the most basic form of cancer registration to capture incidence and survival data.

Richard Sullivan, Professor of cancer policy and global health at King’s College London, has recently said that the current regulatory environment for clinical research may be responsible for delaying the development of new drugs. Why are these research regulations necessary and do you think they are too strict?

Regulation of research is, of course, absolutely necessary, especially clinical trials where one is taking new compounds that may have unexpected side effects into children for the first time. However these regulations need to take into account the pre-existing knowledge of use of the drug in adults and also the long established track record of the clinical trial groups in applying complex intensive treatment regimens in children with cancer.

Much of the bureaucracy and expense of running clinical trials comes from the obligations on sponsors to provide drugs free of charge and to report all significant toxicities in a timely manner. However many of the side effects of the backbone treatment to which a new drug may be added are entirely predictable.

Hence, the childhood cancer research community is calling for there to be a proportionate understanding of the risk of trying a new treatment versus the risk of not having an effective treatment for the life threatening disease from which the patient is already suffering. This is especially important in Europe where the clinical trial regulations are currently under revision.

What needs to be done to speed the development of new cancer treatments for children?

In order to accelerate the introduction of innovative treatments into childhood cancer, we need a new relationship with industry and with regulators. In both North America and Europe, changes in the processes for approving new drugs have tried to incentivize the pharmaceutical industry to support clinical studies in children – not just in cancer, but for children with other diseases – to allow children earlier access to innovative treatment.

But these incentives have had a limited effect, certainly in Europe, where the paediatric investigation plans that have been approved often bear little relation to the clinical unmet needs of children with cancer.

At present, a pharmaceutical company applies for approval of a new drug based on the disease rather than the molecular mechanism it targets. So if they say the drug has been primarily developed for lung cancer, for example, as has been done with ALK inhibitors, then they may apply for a waiver from conducting any paediatric studies, as lung cancer does not occur in children.

However, the molecular mechanism is targeted, the anaplastic large cell lymphoma kinase, is also mutated in neuroblastoma, which is a childhood cancer.

One thing that needs to happen is for the childhood cancer research community to develop a stronger influence with industry in order to give us access to the most interesting compounds that target molecular pathways in common with adult cancers, both for pre-clinical research and for early phase trials.

We also need to work with the regulatory authorities to improve the approach to waivers and use of pre-existing data on the safety and toxicity of the backbone therapies alongside which new drugs may be tested.

The other challenge in Europe is that currently a pediatric investigation plan requires that a company thinks about the possible development of the drug for use in children, from early to late phase trials, even before the first steps have been completed. This is inhibiting companies from investing in pediatric studies, even voluntarily, because the timescales are very prolonged, drug development is very expensive, there is still a substantial risk that the drug may not be effective in that setting, and, of course, the ultimate market is not generally considered financially attractive in such rare diseases.

How do childhood cancer survival rates compare to those of adults?

They remain superior, certainly in high income countries. Survival from adult cancer varies by subtype and by country but if you take all adult cancers together, then between 50-65% can expect to be alive five-years after diagnosis. For children in this setting, the variation between well-resourced countries is smaller and overall survival is ~ 80%.

Why is there little economic incentive for pharmaceutical companies to develop anticancer drugs adapted for children?

The financial incentive offered by the marketing authorisation procedure is seen as insufficient, because of the enormous cost of developing a new drug and the very small market for a drug targeted only at a childhood cancer or a paediatric-specific molecular target. The development costs would be proportionately higher as the clinical trials required to take a drug to market would have to be opened in several centres across many countries, due to the rarity of the individual childhood cancer subtype.

There is also very little incentive for industry to develop child-friendly formulations or to do trials that improve pharmaco-kinetic, safety and efficacy information for labelling purposes of already marketed drugs. Again, the extension of patent-protection (6 months) is viewed as insufficient and the timescales required to do the trials, too long for this type of research to improve treatments to be undertaken by main stream industry.

However, shared risk taking between clinical academia (with good access to the patient population in clinical need) and smaller biotech companies has borne fruit in a few limited areas, albeit with a high risk that the continued development of the compound may not be financially sustainable.

How important do you think establishing open collaborations with many groups will be in speeding up drug development?

I think this is essential. In order to get industry to be more interested in developing new drugs for children or testing their existing drugs to see if they are active against childhood cancer, the clinical and academic world has to have a cohesive partnership with involvement of parents and patients, ready to work with industry. This means academic collaboration across countries is essential.

How many childhood cancer survivors currently experience long-term consequences of cancer treatment and how do you think this number can be improved?

A lot of research has been and continues to be done on the health status of people who have been treated for cancers in childhood, anywhere between 5 years and 40 – 50 years ago. With long term follow up, quite a high proportion will report life-limiting physical and mental health problems. This is clearly very important as it is estimated that more than 1 in 1,000 adults in high income countries has now survived childhood cancer.

The proportion who report long term side effects varies by the type of treatment received, some of which are no longer in such common use, such as radiotherapy to the brain in a very young child.

Whilst it’s well documented that a high proportion of childhood cancer survivors will report chronic health problems, there are two ways this can be ameliorated. One is now that we’ve done the research to quantify what the risks are of having these long-term chronic conditions, it means that young people just coming off treatment can be educated about what they need to look out for.

It may well be that adaptations to their lifestyle might reduce the risk of them having some of these problems, so they can be well informed and there may even be treatments that help reduce the risk of side effects happening.

But much more importantly, we need to be able to decide on the best treatments for each individual child based on the biology of their tumor. That means that we can potentially avoid giving them some of the treatments that we know have a serious risk of side effects such as radiotherapy, drugs that damage the heart, drugs that damage the kidney.

So we can reduce treatment for some of the good risk groups, shifting the focus of front line therapy from “cure at any cost” to “cure at a reasonable cost”. However, this is a fine balance, as many of these chemotherapy drugs remain essential components of the currently available anti-cancer armamentarium. Maximising the success rate of first line regiments is important, as side effects are much greater for an individual who has needed treatment for relapse.

We also need to remain alert to the possible long term side effects of targeted agents, that are only just starting to be used in children with the worst prognosis cancers. Setting up prospective data collection as new drugs are increasingly used more successfully will be essential.

Please can you explain what multidisciplinary care is and why it is important to childhood cancer patients?

Caring for children with cancer requires a Multidisciplinary and multiprofessional team effort. This means that doctors of many specialities (haemato-oncologists, surgeons, radiotherapists, radiologists, pathologists, palliative care & symptom management) work together with specialist nurses, rehabilitation experts, psychological support and educational staff to give the children and their families expert diagnosis and treatment within a holistic package of care. This should empower the family to be an active part of their child’s treatment and recovery.

The most rapid way for countries to make progress in improving childhood cancer treatment is to support doctors, nurses and other health professional groups to develop subspecialist interests and have training opportunities together focused on addressing the needs of children with cancer.

Where can readers find more information?

They can find our paper and the accompanying editorial on The Lancet Oncology: http://www.thelancet.com/series/childhoodcancer

About Prof Kathy Pritchard-Jones

Professor Kathy Pritchard-Jones is Professor of Paediatric Oncology at University College London’s Institute of Child Health and Great Ormond Street Hospital, London.

After completing a PhD in the molecular biology of Wilms tumour in Edinburgh, she has spent over 20 years in clinical and translational research in childhood cancer, much of it at the Royal Marsden Hospital and the Institute for Cancer Research in Sutton, Surrey, UK.

She is leading the European effort to introduce a biology-driven approach to improving the treatment of childhood renal tumours through the SIOP Renal Tumours Study Group (www.siop-rtsg.eu).

She is part of the executive leadership of the European Network of excellence for Cancer Research in Children and Adolescents (www.encca.org). This European commission FP7-funded project aims to create a sustainable infrastructure for international collaborative research across Europe to improve cure and quality of cure for children and young people with cancer.

Her major interest in national and international partnership working has led her to apply this experience to the field of adult cancers. She combines her work in childhood cancers with a senior leadership role in cancer strategy at UCL Partners, one of five academic health science systems in England. A major part of this role is as Chief Medical Officer for London Cancer, an integrated cancer system involving 12 hospitals in North London and serving a population of over 3.2 million.

Her ambition is to make a step change in cancer patient outcomes and experience in London, through focusing on ensuring equitable access to best practice and innovation and understanding the value of the whole pathway.

cancer

via cancer http://cancerwebs.blogspot.com/2013/09/child-cancer-survival-interview-with.html

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