Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries.
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von Hoff Katja, Obrecht-Sturm Denise, Ghasemi David R, Wenning Janna, Mynarek Martin, Gerber Nicolas U, Benesch Martin, Juhnke Björn O, Bison Brigitte, Warmuth-Metz Monika, Timmermann Beate, Faldum Andreas, Tippelt Stephan, Fleischhack Gudrun, Grotzer Michael, Hernáiz Driever Pablo, Beilken Andreas, Ebinger Martin, Graf Norbert, Frühwald Michael C, Schmid Irene, Slavc Irene, Koch Arend, Bergmann Markus, Hagel Christian, Coras Roland, Blümcke Ingmar, Reifenberger Guido, Felsberg Jörg, Keyvani Kathy, Harter Patrick N, Prinz Marco, Staszewski Ori, Acker Till, Stadelmann-Nessler Christine, Hartmann Christian, von Deimling Andreas, Sommer Clemens, Hasselblatt Martin, Riemenschneider Markus J, Monoranu Camelia-Maria, Rushing Elisabeth, Haberler Christine, Kool Marcel, Sill Martin, Pfister Stefan M, Schüller Ulrich, Pietsch Torsten, Kortmann Rolf D, Kwiecien Robert, Witt Hendrik, Pajtler Kristian W, Rutkowski Stefan, German, Austrian and Swiss HIT-Network
Аннотация
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 progression-free survival (PFS) and overall survival (OS) were 62 ± 3% and 81 ± 2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: posterior-fossa group A ependymoma (EPN-PFA) (n = 146): 45 ± 4%/77 ± 4%; posterior-fossa group B ependymoma (EPN-PFB) (n = 19): 90 ± 7%/100%; supratentorial ependymoma, ZFTA fusion-positive (EPN-ZFTA) (n = 59): 64 ± 7%/86 ± 5%; supratentorial ependymoma, YAP1 fusion-positive (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 = .0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (P < .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.