Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.
PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Ramaswamy, V; Hielscher, T; Mack, SC; Lassaletta, A; Lin, T; Pajtler, KW; Jones, DTW; Luu, B; Cavalli, FMG; Aldape, K; Remke, M; Mynarek, M; Rutkowski, S; Gururangan, S; McLendon, RE; Lipp, ES; Dunham, C; Hukin, J; Eisenstat, DD; Fulton, D; van Landeghem, FKH; Santi, M; van Veelen, M-LC; Van Meir, EG; Osuka, S; Fan, X; Muraszko, KM; Tirapelli, DPC; Oba-Shinjo, SM; Marie, SKN; Carlotti, CG; Lee, JY; Rao, AAN; Giannini, C; Faria, CC; Nunes, S; Mora, J; Hamilton, RL; Hauser, P; Jabado, N; Petrecca, K; Jung, S; Massimi, L; Zollo, M; Cinalli, G; Bognár, L; Klekner, A; Hortobágyi, T; Leary, S; Ermoian, RP; Olson, JM; Leonard, JR; Gardner, C; Grajkowska, WA; Chambless, LB; Cain, J; Eberhart, CG; Ahsan, S; Massimino, M; Giangaspero, F; Buttarelli, FR; Packer, RJ; Emery, L; Yong, WH; Soto, H; Liau, LM; Everson, R; Grossbach, A; Shalaby, T; Grotzer, M; Karajannis, MA; Zagzag, D; Wheeler, H; von Hoff, K; Alonso, MM; Tuñon, T; Schüller, U; Zitterbart, K; Sterba, J; Chan, JA; Guzman, M; Elbabaa, SK; Colman, H; Dhall, G; Fisher, PG; Fouladi, M; Gajjar, A; Goldman, S; Hwang, E; Kool, M; Ladha, H; Vera-Bolanos, E; Wani, K; Lieberman, F; Mikkelsen, T; Omuro, AM; Pollack, IF; Prados, M; Robins, HI; Soffietti, R; Wu, J; Metellus, P; Tabori, U; Bartels, U; Bouffet, E; Hawkins, CE; Rutka, JT; Dirks, P; Pfister, SM; Merchant, TE; Gilbert, MR; Armstrong, TS; Korshunov, A; Ellison, DW; Taylor, MD
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