ASTRO 2015

Favourable results seen with radiotherapy for rare paediatric brain and spinal cord tumour

Dr Thomas Merchant - St. Jude's Children's Research Hospital, Memphis, USA

I discussed or presented the results from a prospective clinical trial that involved children with ependymoma, a rare brain tumour.

Why did you look at this ependymoma in particular?

Ependymoma is the third most common brain tumour in children, it affects hundreds of children each year around the world. What’s unique about it is the age at diagnosis is generally young, children are often between the ages of three and five years. Twenty years ago and prior to the development of this trial the standard of care, at least in the United States, was to treat these children with chemotherapy after their initial surgery and the results were not very good.

When was radiotherapy first used to treat ependymoma?

The breakthrough really came in the mid- to late 1990s with the advent of conformal and then intensity modulated radiation therapy using photons. These techniques were obviously developed for adult cancers before that time; we implemented that technology to treat children with brain tumours. Given the young age at presentation for children with ependymoma it seemed like a great opportunity to apply advanced technology to treat these young children and minimise radiation dose to normal brain.

So the trial involved four strata in three different treatments. The strata was the group in which the patients were enrolled. There was a stratum where children with a low grade type of ependymoma in the upper part of the brain, supratentorial brain, when that was completely resected using an operating microscope those children were observed. A very small number of children were enrolled on that stratum, it turned out to be about eleven patients.

There is a second stratum and that was for children with subtotally resected tumours, those were the ones that had more than 5mm of residual disease on their post-operative MRI. Those children were treated with a brief course of chemotherapy, approximately seven weeks, they underwent additional surgery if that was feasible and then they received conformal radiation therapy as outlined in the protocol. The larger group of patients that involved almost 300 of the patients on the study were children with differentiated or anaplastic ependymoma in the upper or lower part of the brain. After near-total or gross total resection those children received immediate post-operative radiation therapy. The dose that they received, 59.4Gy, was considered a very high dose. In this trial we used a very small target volume margin, at the time it was 1cm, we’ve since reduced that or we’re trying to reduce that on some of our current trials. The guidelines were followed in an unprecedented manner by the 115 institutions that contributed patients to this study.

What were the main findings?

One of the key findings is that the outcome for these children, the best group would be those that had well-resected tumours that received immediate post-operative radiation therapy. Their five year event free survival was about 70%, those are excellent results. More importantly, children under the age of three did as well as children older than the age of three, so that prior strategy to use chemotherapy and defer radiation at the time of recurrence, we’ve basically done away with that. Now the backbone strategy to treat ependymoma is to do surgery and radiation therapy. Obviously there is room for improvement, 70% five year event free survival, there’s much to improve there.

The survival, the event free survival, this is recurrence, only about 30% of patients were able to make it to five years without their tumours coming back. More importantly, the overall survival was even higher, it was in the 80% range for the very young children on our study compared to about 40% in older published series. So we’ve more than doubled the survival for children with ependymoma based on the strategy that was outlined in this protocol that we recently completed.

What about the tolerability and safety of using radiation in children?

The breakthrough, as I talked about, came in the mid to late 1990s with the advent of conformal and intensity modulated radiation therapy but the breakthrough was also a pilot study that was performed at St Jude Children’s Research Hospital during that time. We published that in The Journal of Clinical Oncology in 2004 and later updated our series in 2009 in Lancet Oncology. What we found is not only excellent event free and overall survival in children of all ages, and this again is from the pilot data from St Jude, but we also published functional outcomes looking at neurologic, endocrine and cognitive outcomes in these very young children. So I think we’ve documented very carefully the safety of advanced radiation in very young children. In the study that I presented yesterday we also have a number of biologic aims and functional outcome aims, we’ve collected that data, we’ve collected that tissue and the analysis is currently ongoing.

What else would you like to highlight from the trial?

The important thing here is that this was a very unique group of patients, very young, treated with high dose radiation therapy with excellent outcomes. It has set an example for other tumour types that include very young children that radiation may be safely delivered even very soon after their initial diagnosis.

What would be your take home message?

I think that those who are involved in research, brain tumour research, have known for some time what the results would look like from this study; obviously this was the final presentation. So investigators have a good understanding of the work that we’ve done, it’s now become a standard of care and so current trials and future trials use what we’ve done as a backbone and we’re looking for newer ways to improve disease control and functional outcomes in these children. Europeans launched a trial for ependymoma this year that includes not only what we’ve done as a backbone but further escalation of radiation dose for high risk patients. In the United States we’re currently testing the benefit of chemotherapy given after radiation therapy to improve that event free survival that I reported as 70% in the more favourable cases.