A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups

Abstract

Background Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach. Methods and materials We analyzed 302 pediatric ependymoma cases. Tumor, demographic, and treatment variables were investigated for association with relapse risk, time to recurrence, and survival after relapse. DNA methylation profiling was performed for 135/302 cases, and predominant subgroups were EPN_PFA (n = 95) and EPN_RELA (n = 24). Chromosome 1q status was ascertained for 185/302 cases by fluorescent in‐situ hybridization (FISH), multiplex ligation‐dependent probe amplification (MLPA), and DNA methylation profiles. Results Sixty‐two percent of cases relapsed, with a median of two recurrences with no difference between posterior fossa and supratentorial locations (66% vs 55% relapse rate). One hundred seventeen (38%) cases relapsed within two years and five (2%) beyond 10 years. The late relapses were clinically heterogeneous. Tumor grade and treatment affected risk and time to relapse variably across subgroups. After relapse, surgery and irradiation delayed disease progression with a minimal impact on survival across the entire cohort. In the EPN_PFA and EPN_RELA groups, 1q gain was independently associated with relapse risk (subhazard ratio [SHR] 4.307, P = 0.027 and SHR 1.982, P = 0.010, respectively) while EPN_PFA had increased relapse risk compared with EPN_RELA (SHR = 0.394, P = 0.018). Conclusions Recurrent pediatric ependymoma is an aggressive disease with poor outcomes, for which current treatments are inadequate. We report that chromosome 1q gain increases relapse risk in common molecular subgroups in children but a deeper understanding of the underlying biology at relapse and novel therapeutic approaches are urgently needed.

Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma

“…Libraries were sequenced on an Illumina HiSeq machine targeting 50 million reads per sample and aligned to the human genome (Hg19) and transcriptome using TopHat2 and summarized at gene level using FeatureCounts. DNA Methylation analysis for the RNA-seq dataset was performed as previously described [ 6 ]. Samples were normalized to log2 transcripts per million (log2TPM) for visualization.…”

“…Contemporary standard-of-care treatment for ependymoma patients is surgery followed by focal radiotherapy [ 5 ]. Despite this, 40–60% of these tumors will recur at the primary site of disease or with metastatic spread [ 4 , 6 ]. The role of chemotherapy in this disease remains uncertain and is currently being investigated in several international clinical trials (clinicaltrials.gov identifiers: NCT01096368 and NCT02265770) [ 7 , 8 ].…”

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up

“…Even after one or more surgical procedures, adjuvant radiotherapy, and sometimes also chemotherapy 2 , progression-free survival (PFS) and overall survival (OS) are still unsatisfactory in the long term. Relapses generally occur in fact within two years after the initial diagnosis, but may also pose a threat to patients' lives even many years later [3][4] .…”

Pediatric ependymoma: an overview of a complex disease

“…However, prognosis of children with recurrent ependymoma remains poor [68]. A recently published retrospective analysis reported an increased risk for recurrence in patients with tumors with gain of chromosome 1q and/or PFA-methylation profile, further demonstrating only little benefit from resurgery and reirradiation in case of relapse [69].…”