Clinical trials have helped to save thousands of children's lives.
Survival rates for children’s cancers are at an all-time high. Forty years ago, 4 in 10 children diagnosed with cancer survived the disease for five years. Now that figure has jumped up to more than 8 in 10, thanks to research.
This increase in survival is a success story for cancer research, but that doesn’t mean there aren’t still improvements to be made.
We still need research to find better treatments for children with cancers that don’t respond, kinder treatments to reduce the risk of side effects, and better ways to identify children who have a high risk of their cancer returning, to tailor treatment to reduce this risk.
One of our researchers, Professor Kathy Pritchard-Jones from University College London, is leading the way to achieving these goals.
Progress is steadily being made and children are now receiving less intensive treatment than they did previously, meaning healthier lives for many survivors. But how has less led to more?
During the last 15 years, clinical trials have helped researchers tease apart the therapies that give real survival benefits from those that don’t, reducing unnecessary treatment.
On top of that, researchers have been finding ways to work out which tumours likely will or won’t respond to treatment, and tailoring the amount given based on this.
Called ‘risk-directed therapy’, this involves grouping patients as either low, intermediate, or high risk, referring to the likelihood that treatment will work and how likely the cancer will return. These groups are based on the cancer’s stage and how its cells look under the microscope.
If the tumour is packed with lots of immature cells that have refused to grow up as they should have, then generally the outlook is not good and the patient’s tumour is high risk. Fortunately, this is the case for only a small proportion of patients and the majority are classified as low or intermediate risk.
“Research has led to more and more children being accurately grouped and therefore successfully treated with the minimum amount of therapy they need,” said Pritchard-Jones.
“We now have a consistent, intense treatment strategy for those in high risk groups, which has made a real difference. Historically none of these patients would have survived – that’s now increased to around one-third of patients.”
But while advances have been made, this strategy of personalising treatment still needs to be refined. Because much like the weather, forecasting outcomes for patients isn’t perfect and the way these tumours behave can still be hard to predict.
Don’t judge a tumour by its cover
One group helping to lead the way on improving Wilms’ tumour treatment is the International Society of Paediatric Oncology (SIOP) Renal Tumours Study Group. In the latest of their series of trials, headed by Pritchard-Jones, the researchers found that a chemotherapy drug called doxorubicin wasn’t needed in most patients with intermediate risk tumours.
That was a really important find, because although it’s an effective anti-cancer drug, doxorubicin can sometimes be harmful to the heart.
Some patients who were given doxorubicin as part of their chemotherapy and were cured of their cancer suffered heart failure later on in life, despite appearing healthy for a number of years.
But the potential for health problems later in life isn’t limited to children who have been given doxorubicin. Studies have shown that at least 6 in 10 children who have survived cancer develop long-term health issues as young adults.
Radiotherapy, for instance, can sometimes alter growth and development and affect fertility. But again trials comparing different doses of radiation on Wilms’ tumour patients with different stages of disease have helped optimise the therapy to avoid giving too much or too little.
In spite of what has been learnt though, there is still a need for a greater understanding of the disease’s biology. That’s because, paradoxically, most patients whose tumours come back have low or intermediate risk cancers that haven’t spread. And about half of recurrences are fatal.
Clearly things are not so black and white, and there is more to a tumour than meets the eye.
That’s why researchers have been digging a little deeper and looking at what’s going on inside tumour cells. More specifically, in their DNA.
Extending the alphabet
Cancer is a genetic disease, driven by ‘spelling mistakes’ in our DNA alphabet that cause cells to grow out of control. In some cases of Wilms’ tumour, these errors occur in a gene that was actually named after the disease – WT1.
WT1 is what’s called a ‘tumour suppressor gene’, meaning it helps to prevent cells from developing into cancer. But if it’s faulty, it can actually help tumours develop.
There are other genetic changes that have also been linked with Wilms’ tumours, a number of which involve DNA on chromosomes 1 and 11. And some of these changes have been linked with disease outcome and the likelihood that the cancer will come back.
A loss of DNA letters on chromosomes 1 and 16, for instance, has been linked with poor prognosis and is therefore used by some as a ‘biomarker’ to guide treatment decisions.
Recent work also suggested that having more DNA letters than normal on part of chromosome 1, so called ‘1q gain’, might be associated with poor outcome. So Pritchard-Jones and colleagues decided to look into this in more detail in their latest study, published yesterday in the Journal of Clinical Oncology.
After combing through the DNA of almost 600 patients with Wilms’ tumour, the researchers found that 1q gain was indeed linked with slightly worse survival.
Alterations to other genes that are commonly faulty in cancer, like p53, were also linked with slightly lower survival.
But on their own, none of these flawed genes were associated with substantially fewer patients surviving.
So the team thinks that multiple genetic changes, alongside cell analysis and cancer stage, should together be used to accurately group patients by risk and help guide their treatment.
And that’s what Pritchard-Jones and her team plan to look at in their next trial, due to open this year.
“We now want to understand how we can combine these genetic markers with clinical risk so that we can better select children who only need the standard treatment, rather than intense strategies with more side-effects,” she said.
But it seems they may also need to add another element to their investigation.
In a separate study, Pritchard-Jones and colleagues found that individual Wilms’ tumours have a lot of genetic diversity, and certain genetic faults weren’t present in every sample taken from the same tumour. That’s an obvious problem if only one sample is taken for each patient, which is currently the standard for clinical trials.
A way to get round this, Pritchard-Jones says, could be to collect samples of cancer cell DNA that have been spat out of the tumour and float around in the patient’s blood – circulating tumour DNA. These may give a broader picture of the tumour’s genetics than biopsy samples can offer.
Clearly a lot of progress has been made over the years, and moving towards such a personalised approach to treatment is one of Cancer Research UK’s top priorities. Not just for Wilms’ tumours, but other cancers, too.
Ultimately, tailoring and optimising are already bringing about kinder treatments with fewer side effects, and in the future this approach will help even more people survive cancer and live healthier lives beyond it.
- Cresswell, G., et al (2016). Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications EBioMedicine DOI: 10.1016/j.ebiom.2016.05.029
- Chagtai, T., et al (2016). Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study Journal of Clinical Oncology DOI: 10.1200/JCO.2015.66.0001