Pediatric ependymoma: New perspectives on older trials

Pediatric ependymoma remains a highly morbid CNS malignancy which relapses in over 50% of patients. Relapsed ependymoma is often treated with multiple surgeries, re-irradiation, and salvage chemotherapy, all with a low chance of cure.¹ Uniquely among pediatric brain tumors, there is a significant drop from 5-year survival (~75%) to 10-year survival (~60%), likely owing to the protracted clinical course of patients with multiple relapses.²

Prevention of relapse thus remains the key goal for newly diagnosed pediatric ependymoma. Multiple studies over the past decades have confirmed that complete resection and subsequent focal radiotherapy correlate with improved event-free survival (EFS) and overall survival (OS), and should be considered standard of care.³ However, the survival benefit of chemotherapy remains in question. Although there is now some evidence from the COG ACNS0831 trial that maintenance chemotherapy may be helpful after gross total resection (GTR),⁴ the role of chemotherapy in patients with subtotal resection (STR) remains uncertain.

The SIOP group now reports results from the first large, prospective pediatric ependymoma trial, SIOP Ependymoma I.⁵ Patients were enrolled between 1999 and 2007 and were followed for a median of 12 years. Although much has changed since the trial was designed, including standards for both surgical resection and radiation therapy, we can still gain valuable insights.

Seventy-four patients, 3-21 years old with nonmetastatic intracranial ependymoma, were treated on the SIOP Ependymoma I protocol. The primary outcomes were (1) 5-year EFS and OS of a staged management strategy (radiotherapy only for patients with GTR, chemotherapy + radiotherapy for patients with STR) and (2) the response rate to a chemotherapy regimen, including vincristine, cyclophosphamide, and etoposide (VEC) after STR. Concordant with other published clinical trials,⁶ GTR was associated with better EFS and also showed a trend toward better OS. However, the only statistically significant predictor of OS was tumor grade. Interestingly, the authors note that upon retrospective radiological review, up to twice as many patients would have qualified for second-look surgery as occurred in the study. Adherence to the chemotherapy regimen was a challenge despite clear study protocols, similar to what has occurred in other studies. Only 29 of the 41 patients in the STR group received chemotherapy. Of those 29, 65% had a complete or partial response. This is similar to the 67% response rate seen with a cisplatin-containing regimen after STR in the COG ACNS0121 trial.⁷

Although the cohort was enrolled well before the molecular era, the authors performed extensive post hoc molecular subtyping⁸ on as many of the tumor specimens as possible. This increases the applicability of the data from this study to future trial designs that are based on molecular subtyping. The study confirmed previously noted associations of chromosome 1q gain, hTERT expression, and loss of H3K27me3 with worse outcomes.

The study was not designed to address whether or not chemotherapy improves EFS or OS, which remains a key question for pediatric ependymoma. The role of ependymoma subtyping in clinical decision making also remains an active area of investigation, and this study was only able to add confirmation of known associations given the small numbers of patients with specific ependymoma subtypes. The main takeaway from SIOP Ependymoma I is that the VEC regimen may be a reasonable option after STR, offering patients with unresectable ependymoma an opportunity for durable disease response. It remains to be elucidated whether adjuvant chemotherapy following STR facilitates greater extent of resection or improves OS in pediatric ependymoma. Further analysis of COG ACNS0831 data and results from the ongoing SIOP Ependymoma II trial will hopefully shed more light on these questions in the future.

Acknowledgments

This text is the sole product of the authors, and no third party had input or gave support to its writing.

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