A perfect storm

Globally, one child per million is diagnosed with high-risk neuroblastoma every year. Solving Kids’ Cancer is working to ensure that child can beat the odds

The most common extracranial solid tumour in childhood, and arguably one of the least well-known, neuroblastoma is a cancer of the sympathetic nervous system which occurs in infants more often than any other tumour type.1 Typically characterised by tumours in the adrenal glands or abdomen, neuroblastoma is diagnosed in just two children per million every year, most of them under the age of five, and half of them classified as high risk.

Diagnosing  neuroblastoma

The rarity of neuroblastoma is such that the overwhelming majority of paediatricians will never encounter a case, a fact which makes diagnosis a difficult and often lengthy process.

“The symptoms are so vague at first that clinicians usually assume they are the result of a virus or ‘growing pains’ – something typical for a child of that age,” explained Donna Ludwinski, director of research programmes at Solving Kids’ Cancer (SKC), a US- and UK-based charity which supports families affected by and funds innovative research into high-risk childhood cancers. “What that ultimately means is that by the time a child is diagnosed with neuroblastoma, the tumour has often already spread.”

In Europe, around 1,500 children are diagnosed with the disease each year. While about half will be deemed low- and intermediate-risk cases with a good prognosis hovering at a 90% survival rate, the remaining 750 will face an anxious and uncertain future filled with intensive courses of chemotherapy, surgery, radiation, stem cell transplantation, and months of immunotherapy.


“Neuroblastoma is so heterogeneous that around half of all cases actually have a very, very good prognosis,” Ludwinski said. “The neuroblastoma will spontaneously regress in many low-risk cases without any treatment. But for children in the high-risk group, who are usually around 18 months or older, by the time of their diagnosis the disease has often already spread to the bones and bone marrow, perhaps even the lungs and liver, and it will be very difficult to treat.”

Many of these children will prove resistant to initial therapy and will never reach remission. A number of those that do will go on to relapse. Only half will survive for five years after their diagnosis.

A major difficulty, Ludwinski explained, lies in the metastatic nature of the high-risk disease, which makes it far harder to treat than blood cancers such as leukaemia or localised solid tumours. The result is that survival rates for high-risk neuroblastoma have seen only incremental increases in recent years.

Funding challenges

Nonetheless, there is cause for hope. In 2015, the European Medicines Agency (EMA) gave the green light to trial the so-called ‘orphan medicine’ dinutuximab for the treatment of high-risk neuroblastoma patients aged between one and 17. Its decision followed a clinical trial which saw 66% of patients treated with a dinutuximab-immunotherapy-isotretinoin combination free from recurrence or tumour growth after two years, compared to just 48% of those treated with isotretinoin alone.

This game-changing antibody therapy could increase as many as a third of high-risk neuroblastoma patients’ chances of survival in the UK, but any celebrations were called to a halt in November last year, when the National Institute of Health and Care Excellence (NICE) opted not to recommend its funding, a decision which will force high-risk children to look overseas for options if they have any hope of benefitting from the drug, Ludwinski said.


She explained: “To put that decision into context: NHS England has a budget of £120bn (~€160.4bn) for 2016-17; if every child who needs it were to receive dinutuximab at full price, it would cost £2m, or 0.0017% of the budget. That’s a total cost to the taxpayer of just 2.5p a year.”

SKC believes this decision is unreasonable in the light of the evidence submitted and in July lodged an appeal on the basis that NICE acted unfairly and beyond its legal powers.

A recent case in the UK has inspired reason to be optimistic. In March, NHS England claimed it did not have the power to fund PrEP (pre- exposure prophylaxis), a once-a-day drug which has proven highly effective at preventing HIV when taken regularly. UK AIDS charity the National AIDS Trust (NAT) took that decision to the High Court, which in August agreed that NHS England can legally fund the drug. For Stephen Richards, who joined SKC as CEO in July, the victory is an important milestone.

“It highlights the possibility of charities working together more on points of principle where the decision has been made that the numbers are too small and the costs too high,” he said. “After all, there are huge human rights issues at stake here which shouldn’t be forgotten about because the numbers are so tiny.

“It also raises important questions about the way funding decisions are made. The methodology used to assess whether drugs should be available to adult populations is not very easily translated to children, especially where the numbers are small. We believe the methodology NICE uses was rather inflexible and should be more in tune to the population it is looking at at any particular time.”

“Another unfair factor, in our opinion, was NICE’s insistence on the use of ten-year data,” Ludwinski added. “Both the Food and Drug Administration and EMA routinely use much shorter spans in the evaluation of efficacy.2 … It put us at a huge disadvantage because there are so few children followed at that ten-year point that the data just isn’t statistically significant. But the evaluators used it as grounds to say that they can’t prove the drug makes a difference at ten years – well, the numbers are so small that you can’t prove it doesn’t make a difference, either. It took more than 25 years to develop and test this agent, and it is the first drug ever approved for neuroblastoma. It is very important that this antibody is made available to children in the UK.”

International research

The appeal is just one example of the work Solving Kids’ Cancer does to ensure children with high-risk neuroblastoma have access to the best possible treatment options. Alongside UK charity J-A-C-K and Solving Kids’ Cancer US, SKC is a founding member of the International Neuroblastoma Research Collaboration for Effective Delivery (INBRACED),   a partnership between charities, researchers and clinicians which aims to accelerate the development of new, more effective neuroblastoma therapies. It is here that the SKC performs much of its research work.


“SIOPEN (the International Society of Paediatric Oncology European Neuroblastoma) has really made Europe the model for international clinical trials because it has already cleared a lot of the regulatory hurdles that come with countries running trials together,” Ludwinski said. “INBRACED is really now trying to take that attitude of co-operation and translate it to the US.

“When conducting clinical research in rare diseases, international trials are essential in order to accrue patients in a reasonable time frame. What we’d like to see is more co-operation between countries and more research advocate involvement in clinical trial and design.”

INBRACED is also keen to introduce international phase one studies, a controversial decision given their often small nature. “Phase three trials can be very big and very expensive, whereas phase one trials are small and typically done in a single institution,” Ludwinski explained. “That means it can be very difficult to do the necessary data collection where they’re performed in various places, but we’d like to use our influence to really push those boundaries and introduce phase one studies across the Atlantic.”

Ludwinski and Richards are hopeful that this will help to accelerate the development of effective neuroblastoma therapies and get promising new drugs to the children who need them much sooner.

Upcoming trials

Two upcoming trials, which SKC is jointly supporting, hold particular promise. The first is a Pfizer-produced ALK (anaplastic lymphoma kinase) inhibitor which has already tested very effectively for the treatment of lung cancers and could prove similarly successful for as many as 15% of high-risk neuroblastoma patients.

Children in Europe will take part in a phase one dose escalation trial at sites in the Royal Marsden Hospital, UK, and Paris, France, while US children will participate at around 14 sites across the country. That study will be immediately followed by a single-arm phase two trial, which SKC is hopeful will end with Pfizer being given approval for use of the drug in neuroblastoma therapy.

A second trial will evaluate the effectiveness of a targeted radiation compound known as metaiodobenzylguanidine (MIBG) in combination with immunotherapies. The study, which will be held at four sites across the UK (Southampton and London), the US (Wisconsin) and Germany, marks the first time the abscopal effect of radiation and immunotherapy has been investigated in children and is expected to open in mid-2017.

Support services

In the meantime, SKC is committed to supporting the children and families in the UK living with neuroblastoma. Many of its team have personal experience of caring for children with the disease and so are well-placed to offer guidance and support to parents and carers coming to terms with the diagnosis for the first time. In some cases, that extends to visiting a family at home or accompanying them to a consultation, and making sure they have all the information they need to make informed decisions for their child.

“Because so few healthcare professionals will come across neuroblastoma in their careers, it’s very important that families feel supported, are informed and are aware of their options,” Richards said. “Not just in terms of treatment in the UK but also when it comes to the availability of trials abroad. A number of our team can act as advocates on a family’s behalf to ensure they have access to the relevant care, and we also have access to negotiators to help them get the best value from hospitals. Medical expenses can range anywhere from £250,000 to upwards of £500,000, so, where necessary, we also help to raise the required funds for a child to receive treatment abroad.

“It’s all about making sure every child with high- risk neuroblastoma has access to the best possible care and the highest possible chances of survival and a good quality of life.”

Looking to the future, one of the charity’s main priorities will be to build up a research base on the familial impact of neuroblastoma. With this in mind, each year SKC holds a parent education conference which offers families the chance to meet and share experiences, as well as an opportunity to speak to world-leading clinicians and researchers about the latest developments in the field of neuroblastoma.

“Having a child with this disease can put an enormous emotional and financial strain on a couple, it can mean they have to give up work for a time, and it can have a big impact on a child’s siblings, so supporting them through this period is really important,” Richards explained. “I’ve heard fantastic reports from the families who have attended our conference.”

Success stories

“One thing that can happen with the high-risk treatment is that, once it’s over, once the child’s been though very intensive chemotherapy, surgery, high dose or stem cell transplant, radiation treatment and, finally, five or six months of immunotherapy, once that’s done, a really devastating outcome that can happen is an isolated brain relapse which doctors suspect is down to the immunotherapy not bridging the blood/brain barrier.


“Let me give you a tangible example,” continued Ludwinski. “A really devastating outcome after frontline treatment that occasionally happens is a relapse that is confined to the brain. Historically, children who suffer these relapses do not live very long at all, but more recently a hospital in New York has developed a sequence of therapies that have a shockingly good success rate. In fact, the majority of the children who have been treated with this therapy are now surviving long term.”

She continued: “Not long ago, there was a young girl in the UK who suffered such a relapse, and her parents were told that her disease was fatal and that there was nothing that could be done as her consultant was unaware of the promising therapy in New York. We were able to provide information and, with the charity’s help, the family raised enough money to have the treatment, and today she’s a healthy little girl.”

1 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2149659/

2 http://annonc.oxfordjournals.org/content/26/12/2363.full

Donna Ludwinski

Director of Research Programmes

Stephen Richards CEO