SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study
AuthorsRitzmann, T. A.
Chapman, R. J.
Kilday, J. P.
Dineen, R. A.
Pajtler, K. W.
Jacques, T. S.
Paine, S. M. L.
Ellison, D. W.
Grundy, R. G.
AffiliationChildren's Brain Tumour Research Centre, University of Nottingham, UK. Nottingham University Hospitals NHS Trust, UK. Children's Brain Tumour Research Network (CBTRN), Royal Manchester Children's Hospital, UK. The Centre for Paediatric, Teenage and Young Adult Cancer, University of Manchester, UK. The Clatterbridge Cancer Centre, Liverpool, UK. The Christie Hospital Proton Beam Therapy Centre, Manchester, UK. Genetics Unit, ASST Lariana General Hospital, Italy. NIHR Nottingham Biomedical Research Centre. Alder Hey Children's NHS Foundation Trust. Hopp Children's Cancer Center Heidelberg (KiTZ), Germany. Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Germany. Department of Pediatric Oncology, Hematology, and Immunology, University Hospital Heidelberg, Germany. UCL GOS Institute of Child Health, London, UK. Great Ormond Street Hospital for Children NHS Foundation Trust, UK. Department of Pathology, St. Jude Children's Research Hospital, USA. The Hospital for Sick Children, Toronto, Canada.
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AbstractBackground SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3–21 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 Seventy-four 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 = .003, HR = 2.6, 95% confidence interval (CI) 1.4–5.1). Grade 3 tumours were associated with worse OS (P = .005, HR = 2.8, 95%CI 1.3–5.8). 1q gain and hTERT expression were associated with poorer EFS (P = .003, HR = 2.70, 95%CI 1.49–6.10 and P = .014, HR = 5.8, 95%CI 1.2–28) and H3K27me3 loss with worse OS (P = .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.
CitationRitzmann TA, Chapman RJ, Kilday J-P, Thorp N, Modena P, Dineen RA, et al. SIOP Ependymoma I: Final results, long-term follow-up, and molecular analysis of the trial cohort—A BIOMECA Consortium Study. Neuro-Oncology. Oxford University Press (OUP); 2022.
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