Abstract Background Current treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model. Methods Patients aged 0–21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries. Results For 291 trial patients, the 5-year PFS and OS were 62±3% and 81±2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: EPN-PFA (n = 146): 45±4%/77±4%; EPN-PFB (n = 19): 90±7%/100%; EPN-ZFTA (n = 59): 64±7%/86±5%; EPN-YAP1 (n = 4): 50±25%/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and/or subtype EPN-PFA1c/d/e,2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS/OS 75±10%/92±7%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS/OS: 33±6%/64±6%). Among EPN-ZFTA, 11/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS/OS: 36±15%/91±9%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS/OS: 19±16%/57±18% vs. 79±7%/97±3%, p = 0.0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (p 0.0001 for PFS and OS). Conclusions These results strongly suggest the inclusion of molecular parameters into stratification, and the use of distinct treatment strategies within future ependymoma trials.
Hoff et al. (2025) studied this question.