We need better treatments for childhood cancer, with less side effects

The Australian government today announced A$20 million for research to find targeted treatments for childhood cancer. In announcing the grant, for the Zero Childhood Cancer Program led by the Children’s Cancer Institute and Sydney Children’s Hospital, Health Minister Susan Ley said:

Cancer has just passed cardiovascular disease as the leading cause of death in Australia and there is no more tragic diagnosis than when it’s in a child. We’ve invested A$12 billion into research since the year 2000… we know we’ve got more dollars to allocate to this really, really important research cause.

This generous funding will be major step toward finding better treatments for children with cancer. Australians have access to the world’s best treatments, doctors and health systems, yet there is a lack of safe, effective and affordable drugs to treat the most aggressive childhood cancers, such as some brain tumours.

One of main reasons for this is that children’s cancer is a rare cancer. This means it is less economically viable for pharmaceutical companies to search for its causes and develop drugs to treat them.

What’s wrong with current treatments?

Treatment for children’s cancer is more successful than ever. Over 80% of children diagnosed with cancer today will survive. But such success has mostly been achieved by using very old, general chemotherapy and radiotherapy – which has its own costs.

Most child cancer hospital wards are full of children suffering from the side effects of treatment, rather than from the cancer itself. And in the long term, one third of childhood cancer survivors will have a significant health problem from the treatment that cured their cancer.

Further reading: Life interrupted: young people need help moving forward after cancer

This is why teams like ours are working to find drugs specifically targeted to individual tumours. Also known as personalised medicine, targeted therapy uses small molecules to specifically and more effectively hit the gene and protein responsible for the cancer.

A goal of targeted therapy is to only kill cancer cells, while healthy ones are left alone. Obviously this means less side effects - both in the short and long term.

Unlike many adult cancers, childhood cancer is not caused by lifestyle choice or environmental hazards such as smoking. Instead it’s likely a result of genetics and some as yet unknown aspects of the early life environment.

The result is childhood cancers have different gene drivers compared to adult cancer, needing specific drug development.

Why isn’t there more research?

Cancer is the leading cause of death from disease in childhood. About three Australian children or young adults die from cancer every week. Yet overall, cancer in children accounts for only 1% of all cancer incidence.

And that 1% is further broken down into a constellation of more than 100 rare and ultra rare diseases. Some childhood cancers have very small sub-populations. For instance, only two or three children in the United Kingdom have a type of Wilms tumour, found in the kidneys.

Being a rare disease means the market is small and there is no commercial incentive for drug companies to research or develop drugs. On the part of big pharma this is not a crime – their businesses need to be profit-driven.

Further reading: Unfair if rare: should the PBS change the way it lists cancer drugs?

The consequence though is that childhood cancer is under-researched. Drugs specifically designed for childhood cancer are almost non-existent. The drug development process is designed for adult cancer, with clinical trials for children only performed once an adult drug is approved for use, often taking five to ten years from the first human trials.

Prioritising potential drugs to take from the lab to clinical trials is still uncertain. For instance, several new therapies that looked promising in animal trials, have fallen over because the lack of efficacy in a large adult cancer patient population led to pharmaceutical companies losing interest.

Of the 120 drugs approved by the United States Food and Drug Administration between 1948 and 2003, only 30 have been used in children.

And despite the anaplastic lymphoma kinase (ALK) gene being identified in paediatric lymphoma 22 years ago, drugs that inhibited the gene were only developed for clinical use when they were found to work in adult lung cancers.

What other barriers are there?

Even once the drug has passed the initial stages and has been approved for human trials, there are a number of barriers when it comes to those for child cancers.

For instance, accessing the ALK inhibitor drugs has been difficult. Even though they work well in child cancers driven by that particular gene, there has been a lack of incentive for pharmaceutical companies to apply to license the drug for use in children.

If an adult trial fails, a clinical trial for children will not proceed. It takes a decade or more, multiple clinical trials and around US$1.8 billion, to get a drug to market, with lots of hurdles along the way.

Last month, the Australian government announced reforms that will bring new medicines to the Australian market quicker by piggybacking on drug assessments made by the FDA and regulatory agencies in Europe, potentially making cancer medicines available up to two years earlier.

This is a step in the right direction, but much more needs to be done to advocate for child cancer patients.

Single agent trials of anticancer drugs are unlikely to cure patients due to the cancer’s capacity to mutate and develop resistance to treatment. It is only by using combinations of anticancer drugs that cure is achieved. Moreover, combining several anticancer drugs allows lower doses of individual agents to be used, reducing the side-effects.

Our own research suggests combination therapies, aimed at a single disease, have the greatest chance of success. Yet current early trial systems are mostly conducted with single agents across a variety of cancer types.

Pharmaceutical companies are often reluctant to combine their drugs with agents from their market competitors. This does not serve children well, slowing down the search for optimal treatment regimens in the clinic.

These roadblocks are a global phenomenon. They have led to a huge unmet clinical need for safe and effective cancer therapies for children. The solutions will be complex and will need collaboration between doctors, researchers, governments and pharmaceutical companies, to come up with a new system which advocates for our youngest and most vulnerable citizens.

Glenn Marshall is part of the research team that has received the latest Federal Government grant, NHMRC, CINSW, CCNSW.

David Ziegler works at the Kids Cancer Centre, Sydney Children's Hospital.