Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Ramaswamy, V.; Hielscher, T.; Mack, S. C.; Lassaletta, A.; Lin, T.; Pajtler, K. W.; Jones, D. T.; Luu, B.; Cavalli, F. M.; Aldape, K.; Remke, M.; Mynarek, M.; Rutkowski, S.; Gururangan, S.; McLendon, R. E.; Lipp, E. S.; Dunham, C.; Hukin, J.; Eisenstat, D. D.; Fulton, D.; van Landeghem, F. K.; Santi, M.; van Veelen, M. L.; Van Meir, E. G.; Osuka, S.; Fan, X.; Muraszko, K. M.; Tirapelli, D. P.; Oba-Shinjo, S. M.; Marie, S. K.; Carlotti, C. G.; Lee, J. Y.; Rao, A. A.; Giannini, C.; Faria, C. C.; Nunes, S.; Mora, J.; Hamilton, R. L.; Hauser, P.; Jabado, N.; Petrecca, K.; Jung, S.; Massimi, L.; Zollo, M.; Cinalli, G.; Bognar, L.; Klekner, A.; Hortobagyi, T.; Leary, S.; Ermoian, R. P.; Olson, J. M.; Leonard, J. R.; Gardner, C.; Grajkowska, W. A.; Chambless, L. B.; Cain, J.; Eberhart, C. G.; Ahsan, S.; Massimino, M.; Giangaspero, F.; Buttarelli, F. R.; Packer, R. J.; Emery, L.; Yong, W. H.; Soto, H.; Liau, L. M.; Everson, R.; Grossbach, A.; Shalaby, T.; Grotzer, M.; Karajannis, M. A.; Zagzag, D.; Wheeler, H.; von Hoff, K.; Alonso, M. M.; Tunon, T.; Schuller, U.; Zitterbart, K.; Sterba, J.; Chan, J. A.; Guzman, M.; Elbabaa, S. K.; Colman, H.; Dhall, G.; Fisher, P. G.; Fouladi, M.; Gajjar, A.; Goldman, S.; Hwang, E.; Kool, M.; Ladha, H.; Vera-Bolanos, E.; Wani, K.; Lieberman, F.; Mikkelsen, T.; Omuro, A. M.; Pollack, I. F.; Prados, M.; Robins, H. I.; Soffietti, R.; Wu, J.; Metellus, P.; Tabori, U.; Bartels, U.; Bouffet, E.; Hawkins, C. E.; Rutka, J. T.; Dirks, P.; Pfister, S. M.; Merchant, T. E.; Gilbert, M. R.; Armstrong, T. S.; Korshunov, A.; Ellison, D. W.; Taylor, M. D.

J Clin Oncol. 2016 Jun 9; 34(21):2468-77


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.

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