Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol

Abstract

Background: The clinical management of ependymoma in childhood and adolescence is complex and the clinicobiopathological correlates of outcome remain poorly understood. This international SIOP Ependymoma II (SIOP EPII) trial aims to improve the outcome of patients with ependymoma.

Methods: SIOP EPII includes any patient <22 years at diagnosis with ependymoma, stratified by age, tumor location, and outcome of the initial surgery. Centralized pathology and imaging is required for diagnosis confirmation. SIOP EPII included three randomized studies according to age, postoperative residue, and suitability to receive radiotherapy. Patients ineligible for interventional strata are followed-up in an observational study. The staging phase aims to determine if central neurosurgical and radiological postoperative MRI reviews increase the resection rate. Patients ≥12 months with (i) no residual disease are randomly assigned in a phase III trial to evaluate the efficacy of post-radiation 16-week chemotherapy (VEC + CDDP) on PFS (stratum I); (ii) centrally confirmed measurable inoperable residual disease are allocated to randomized frontline chemotherapy phase II study (VEC vs. VEC + high-dose methotrexate) and considered for a second-look surgery (stratum II). If second-look surgery is not feasible or tumor residuum remains, patients receive 8 Gy-boost radiotherapy after conformal radiotherapy (phase I). (iii) Patients < 12 months (18 months in the UK) or not eligible to receive radiotherapy are randomized in a phase II study to receive chemotherapy (alternated myelosuppressive and nonmyelosuppressive chemotherapy), with or without valproate (stratum III). To overcome the limitations encountered in the preliminary conclusions of the ACNS-0831 study, a SIOP EPII dedicated on-study amendment has been planned to definitively conclude the relevance of maintenance chemotherapy in stratum I. Secondary outcomes include overall survival, quality of life, neuropsychological and neuroendocrine outcomes, safety, and identification of key prognostic biomarkers (BIOMECA).

Clinical trial registration: ClinicalTrials.gov, identifier: NCT02265770.

Keywords: ependymoma; overall survival; progression free survival; randomized controlled trial; treatments.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Leblond, Massimino, English, Ritzmann, Gandola, Calaminus, Thomas, Pérol, Gautier, Grundy and Frappaz.

Figures

Figure 1

General scheme of the SIOP EPII trial. BIOMECA: Biomarkers of Ependymomas in Children and Adolescents.

Figure 2

Imaging of one patient with ependymoma, at different times. (A) At diagnosis. (B) Immediate postoperative imaging. (C) Postoperative imaging after second-look surgery.

Figure 3

Scheme of the three interventional strata. (A) Stratum I: Patients with no measurable residual disease (R0-1-2). (B) Stratum II: Patients with measurable inoperable residual disease (R3–R4), WHO Grade II–III ependymoma, no metastasis. (C) Children <12 months or those not eligible to receive radiotherapy. *Multiple surgeries (more than 2) or poor neurological status; **Dose adaptation for children less than 10 kg. *multiple surgeries (more than 2) or poor neurological status; **dose adaptation for children less than 10 kg.