Researchers are continually working to refine childhood cancer treatment. These efforts ensure that children are getting appropriate therapies but not unnecessary harm from them.
A recent article, published in the Journal of Clinical Oncology, shares the results of a phase 3 clinical trial (named ACNS0331), run by the Children’s Oncology Group in the US. The trial was originally designed to explore whether it’s safe and effective to reduce radiation given to children diagnosed with newly diagnosed average-risk medulloblastoma. This multi-site clinical trial enrolled patients from 2004–14, and included over 500 participants.
“Our understanding of medulloblastoma has evolved tremendously over the last 10–15 years as we’ve come to appreciate the importance of molecular groups,” said the study’s last author Dr Paul Northcott (pictured above, far left), and one of The Brain Tumour Charity’s Scientific Advisors. “It's no longer sufficient to talk about this disease without taking into account the molecular group.”
Since the design of the trial, science has progressed and we know more about medulloblastoma, including the fact that there are at least 4 different subtypes. These four subtypes are grouped because of common traits and are known as WNT, SHH, Group 3 or Group 4.
Funding from The Brain Tumour Charity allowed the analysis, of all medulloblastomas collected during the clinical trial, to be done from samples kept in storage.
Researchers at St. Jude Children’s Research Hospital used the stored pathology samples to perform whole exome sequencing and methylation profiling. This work allowed the researchers to assign each tumour to one of the known medulloblastoma molecular subtypes: WNT, SHH, Group 3 or Group 4. These molecular groups added context to the trial results and helped the researchers draw conclusions based on the most up-to-date scientific techniques.
“A clinical trial like this, which enrolled so many patients over such a long period of time, is incredibly involved,” Dr Paul Northcott said. “We had one chance to do this analysis properly and get every bit of data we could out of this effort. The results of the molecular profiling were well worth it; they’ve provided valuable insight into how different patients will respond to treatment.”
Understanding variation in responses
The purpose of the clinical trial was to test whether it is possible to reduce the dose of radiotherapy from the standard amount, 23.4gy, to 18gy in children 3–7 years old. The study also tested whether overall outcomes would differ if they were given radiation therapy to either the whole posterior fossa or only the tumour area.
When the molecular groups were not considered, the researchers found that the younger children who had the lower dose of radiation were more likely to have tumour-related events like progression, recurrence or bereavement. Additionally, without molecular groups, the team saw no difference in survival when comparing posterior fossa radiation versus tumour only radiation.
“You could take that at face value,” Dr Northcott said. “But the data really becomes meaningful when we break it down by molecular group.”
Molecular groups provide insight
When looking at the effect of reducing the dose of radiotherapy across the molecular groups, the researchers found no difference for WNT and SHH patients. However, they did observe that children in Group 4 who received the lower dose fared significantly worse than those who received the standard dose. For Group 3 there was a slight, but not statistically significant, trend toward a worse outcome with the reduced dose.
Because the WNT and SHH patients responded similarly on low dose radiation, children with those tumours may be good candidates for reduced doses of radiotherapy in future clinical trials.
The molecular analysis we funded also revealed that posterior fossa radiation has no difference to tumour specific radiation in the WNT, Group 3 and Group 4 tumours. But, for patients with SHH medulloblastoma, receiving the whole posterior fossa radiation had significantly worse outcomes than were observed in children who received the tumour specific radiation. This effect wouldn’t be seen if all the molecular subtypes were considered together.
Findings from this study will aid in development of the next generation of clinical trials for children with medulloblastoma at St. Jude and beyond.
To read more about the work we’re funding into medulloblastoma research, including the wider project this work came from, please visit our medulloblastoma research pages here
This story was adapted from material provided by Erin Podolak, Senior Communication Specialist at St. Jude Children’s Research Hospital.