Expert Discusses Molecular Analysis and Treatment Options in Pediatric Ependymoma

Santhosh A. Upadhyaya, MD

Among pediatric patients with ependymoma, investigators found no difference in 4-year survival by molecular subgroups, according to results from the SJYC07 trial presented at the 2018 ASCO Annual Meeting.

Among patients in the posterior fossa A (PF-A) subgroup, progression-free survival (PFS) was 73.7% ± 8.5% compared with 80% ± 20.7% in the supratentorial C11 or f95RELA-fused subgroup and 100% in the supratentorial YAP1-fused subgroup. Investigators concluded the differences were not significant (P = .40).

In patients in the PF-A subgroup with 1q gain (n = 37; 88%), PFS was 80% ± 20.7% versus 73.3% ± 8.9% (P = .15) for those without 1q gain (n = 5; 12%). Overall survival was also similar for those who gained 1q and those who did not (P = .63).

The 6 patients who had subtotal resection before radiotherapy had poorer PFS compared with the 48 patients who had gross total and near total resection (27.8% ± 16.7% vs 81.2% ± 7.5%; P = .049).

Overall, 4-year PFS was 76.5% ± 7.7% and 4-year OS was 91.0% ± 5.4%. Forty-nine (91%) patients were alive at a median follow-up of 3.8 years.

Median age at enrollment was 1.6 years (range, 0.4-3.1). Thirteen (24%) patients had ependymoma histology and 41 (76%) had anaplastic ependymoma.

Lead author Santhosh A. Upadhyaya, MD, a faculty neuro-oncologist with St. Jude Children’s Research Hospital, said that these results show that molecular subtype does not appear to play a role in outcomes for patients with ependymoma, and suggest that chemotherapy can be safely used as bridge to delay radiation treatment in the youngest patients.

OncLive: What was the rationale for the study?

In an interview with OncLive, Upadhyaya discussed how chemotherapy prior to radiation can improve cure rates, the importance of long-term follow-up in this patient population, and emerging research and treatment for pediatric ependymoma.Upadhyaya: The SJYC07 protocol (NCT00602667) was first opened in December 2007 with the primary intention of improving outcomes for young children—in this case, children less than 3 years of age at diagnosis with highly malignant brain tumors, which includes ependymoma. The concept of the trial was that, after a maximal-safe surgical resection at the time of diagnosis, to treat any remaining cancer cells with systemic chemotherapy followed by radiation.

We have known for a while now that radiation produces excellent outcomes for children with ependymomas. However, what we didn't know was, what is the youngest age at which these children can be radiated? One of the aims of the study was also to see if we could use radiation as young as 1 year of age at diagnosis.

Can you describe your findings?

Children who have been diagnosed with malignant brain tumors like ependymomas, after they come to St. Jude Children’s Research Hospital, we treat them with 4 cycles of chemotherapy and our neurosurgeons will, based on MRI findings, determine if these children need another resection to remove as much tumor as possible. All of these children will get radiation to the tumor bed itself without the rest of the brain or the spinal cord being exposed to radiation. It’s a very focal radiation that’s applied to the tumor bed.After 10 years, we can now safely say that some of the goals that we tried to achieve have been reached. One of the more important goals was to treat, and see if these children can be safely radiated starting at 1 year of age. What we have seen, based on the trial results, is that it's possible—children as young as 1 year of age with ependymomas can be safely treated with radiation to improve outcomes.

Second, one of the important considerations when treating children with brain tumors like ependymoma is whether radiation-deferring strategies can be used until the child's brain is matured to a point that radiation can be safely used. One of the subgroups of children who need this are those less than 1 year of age. We have used surgery and chemotherapy as a bridge to get these children up to 1 year of age and then start treating them with radiation.

These results have been exciting for us. We have been able to show that these youngest children can be safely [treated]; the radiation can then be used to improve outcomes.

Third, what we have also seen is that, as molecular advances have been happening in this field, some of these molecular advances have been applied to these tumor samples that we have. We have validated the presence of 3 molecularly distinct groups of ependymomas in this subgroup of patients, which includes the PF-A, ST-RELA, and ST-YAP. However, one important finding [thus far], by following these patients for a long time, is that the more aggressive subgroup of ependymomas, like the RELA-fused ependymomas, seems to have had better-than-expected results on this trial.

How do you manage toxicity in this population?

Now, these are early days yet. We still need to follow these patients long term and see, eventually, how they're going to do. However, there are some results that we can feel happy about, especially the fact that we have been able to use radiation with a large group of children—especially the youngest group of children—and help them improve their outcomes.Long-term side effects from radiation and chemotherapy are still a matter of concern. It is very important that we treat these children with effective modalities of treatment, but there's also concern that some of these kids will develop long-term side effects with radiation, like neurocognitive deficits, endocrine issues, vascular problems, and of course, secondary malignancies.

Once these children finish up with their treatment, we have a very standard protocol of following these children periodically—every 3 months with scans and physical exams. After a certain period, we try to space out those visits to every 4 months or 6 months depending on how far they get out from the treatment. If there are no recurrences, we feel comfortable that we can space out these visits.

These children do require long-term follow-up. These kids with ependymomas sometimes have a tendency to have the tumor come back very late after the treatment is complete—sometimes even beyond the traditional 5-year period. Therefore, these children do require long-term follow-up. That has been 1 of the findings in our trial; we suggest that these children be followed longer than the traditional 5-year period because we have occasional patients in whom the tumor has come back even after 6 or 7 years.

Are there any ongoing trials looking specifically at molecular subgroups?

Therefore, it is really vital that these patients get the continuous care that they need, especially in a center that is well equipped to follow them up for endocrine long-term side effects, neurocognitive long-term side effects, and of course, to keep surveillance and to make sure that this tumor is not coming back.Yes. Over the years, St. Jude Children’s Research Hospital and other centers in collaboration have described various molecular subgroups of ependymomas. As I pointed out earlier, there are 4 main subgroups in children: ST-RELA, ST-YAP, and then the PF-A and posterior fossa B (PF-B) subgroup of tumors.

The PF-B subgroup is generally seen in children over 5 years of age and has very good outcomes. The same is true for the ST-YAP subgroup of ependymomas in that children who have this subgroup of ependymomas generally do very well. There is now discussion in the neuro-oncology community on whether we should consider de-escalating treatment for these patients in order to prevent long-term side effects, while at the same time maintaining their good outcomes. However, I do want to emphasize that, as of today, the use of surgery and radiation is still the standard of care and any changes to this standard should be tried in a clinical trial.

Are than any known risk factors for developing ependymomas?

There are exciting biological details coming out about these tumors. We are learning there are new biological pathways that can be targeted so that, maybe in the future, we could avoid toxic therapies like radiation and chemotherapy for these children and perhaps treat them with more targeted therapy.Most of the children who, unfortunately, are diagnosed with ependymomas, it just happens as a random incident. There is no known predisposition to developing ependymomas other than neurofibromatosis. Unfortunately, we still don't know what causes ependymomas. The majority of [patients] do not have a cancer predisposition, but we haven't been able to identify any other huge risk factors that lead to the development of these cancers.

As far as risk factors for relapse, we now have good evidence to suggest that those children in whom we are able to get all of the tumor out, or at least most of the tumor out, before radiation treatment have the best chances of cure. Sometimes it's tricky because these tumors are located in parts of the brain where the neurosurgeon may not be able to completely remove the tumor.

These are aggressive tumors. They're sticking around…to the nerves and the vessels, so any aggressive attempt at resection sometimes leaves neurological problems which could be permanent. That is one of the biggest challenges that a neurosurgeon faces when he goes in to operate on these children with brain tumors.

One of the things that we have shown on the SJCY07 trial is that, using chemotherapy as a bridge in situations where the surgeons may not have been able to get all the tumor out, using chemotherapy may be able to shrink the tumor a little bit and make it easier when the surgeon goes to operate again before we treat them with radiation, is really feasible. That actually gives these children a better chance at a permanent cure.

What needs to happen next in the treatment of children with ependymoma?

These are some of the challenges we are facing. There is always a challenge when we discover any new drugs, and whether they will eventually penetrate the natural barrier between the blood and brain, and that is also a huge challenge whenever we design any new trials for children with brain tumors.There are some ongoing studies. There is a need for collaboration that doctors and scientists across the world are doing and St. Jude Children’s Research Hospital is part of that collaboration. We hope that we will discover some medications specifically targeting the pathways in ependymomas so that we're not only improving outcomes for these children, but maybe in the future also prevent some complications from the radiation and chemotherapy that these children have to receive.

Upadhyaya S, Robinson GW, Orr B, et al. Outcomes for young children with molecularly defined ependymoma treated on the multi-institutional SJYC07 clinical trial. J Clin Oncol. 2018;36 (suppl; abstr 10548).