SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study

Ritzmann, Timothy A; Chapman, Rebecca J; Kilday, John-Paul; Thorp, Nicola; Modena, Piergiorgio; Dineen, Robert A; Macarthur, Donald; Mallucci, Conor; Jaspan, Timothy; Pajtler, Kristian W; Giagnacovo, Marzia; Jacques, Thomas; Paine, Simon; Ellison, David; Bouffet, Eric; Grundy, Richard G

Abstract

Background
SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3 to 21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers.

Methods
74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT ,ReLA, Tenascin-C, H3K27me3 and pAKT status were evaluated.

Results
Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding the prespecified 45%.

Conclusions
Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss and hTERT expression were all associated with poorer survival outcomes.

Citation

Ritzmann, T. A., Chapman, R. J., Kilday, J., Thorp, N., Modena, P., Dineen, R. A., …Grundy, R. G. (2022). SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study. Neuro-Oncology, 24(6), 936–948. https://doi.org/10.1093/neuonc/noac012

• Journal Article Type: Article
• Acceptance Date: Jan 4, 2022
• Online Publication Date: Jan 9, 2022
• Publication Date: 2022-06
• Deposit Date: Jan 5, 2022
• Publicly Available Date: Jan 13, 2022
• Journal: Neuro-Oncology
• Print ISSN: 1522-8517
• Electronic ISSN: 1523-5866
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 6
• Pages: 936–948
• DOI: https://doi.org/10.1093/neuonc/noac012
• Public URL: https://nottingham-repository.worktribe.com/output/7165393
• Publisher URL: https://academic.oup.com/neuro-oncology/article/24/6/936/6501464