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

Abstract

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. MethodsFour 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. ResultsMolecular 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. ConclusionThe 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. INTRODUCTIONEpendymoma is the third most common posterior fossa tumor of childhood and a major cause of morbidity and mortality in pediatric oncology, occurring across the entire age spectrum. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Current therapy for posterior fossa ependymoma in children is aggressive surgical resection followed by involved-field radiation, resulting in 7-year event free-survival of 65%. 12,15 Despite the high mortality rate, trials of cytotoxic chemotherapy have failed to reveal a clear survival benefit for chemotherapy over surgery and radiation alone, although definitive pediatric randomized trials of maintenance chemotherapy are still recruiting through cooperative groups (ClinicalTrials.gov identifiers: NCT01096368 and NCT02265770). 1,5,17 In adults, posterior fossa ependymoma is frequently treated with surgery alone. 18Numerous publications have suggested that the most powerful prognostic factor for posterior fossa ependymoma is the extent of surgical resection or, more appropriately, the amount of residual tumor after surgery. This has entailed an aggressive surgical approach, with some oncologists and surgeons tolerating serious neurologic deficits, including the need for tracheostomies and gastrostom...

Case-based review: ependymomas in adults

“…A recent series of 820 patients with infratentorial ependymomas from 4 institutions (83% were EPN_PFA and 17% EPN_PFB) demonstrated that GTR improved PFS and OS for both subgroups. 64 Few patients with EPN_PFA did not receive RT, and RT continues to be recommended because of the poor prognosis. Patients with EPN_PFA tumors and STR fared particularly poorly despite RT, and further research is needed to improve prognosis in this group.…”

Clinical Characteristics and Prognostic Factors of Treatment in Pediatric Posterior Cranial Fossa Ependymoma

“…There is no doubt regarding which factors have the strongest influence on survival from ependymoma since previous studies have confirmed that the molecular subgroup bears the advantage in the prognostic outcome of posterior fossa ependymoma, showing that PFB ependymoma prevailed over PFA in survival [9]. However, there are still other factors that have an influence on the prognostic value of these potential predictors.…”

“…Both posterior fossa type A (PFA) and posterior fossa type A (PFB) still benefit from an increased extent of resection [9]. The internationally accepted management protocol involves surgical resection aiming at gross total resection (GTR) followed by radiotherapy to the tumor bed [10].…”

Put away your microscopes: the ependymoma molecular era has begun

“…Molecular profiling of multiple large ependymoma cohorts (namely through Illumina DNA methylation analysis) has allowed for analyses to be made on the impact of molecular subgroup and clinical variables[5,9,11]. A study of four distinct PF ependymoma cohorts revealed that while use radiotherapy is effective in the case of PF-EPN-A tumors that were gross-totally resected, it had limited impact in patients harboring PF-EPN-A ependymoma with a sub-total resection[5].…”

“…A study of four distinct PF ependymoma cohorts revealed that while use radiotherapy is effective in the case of PF-EPN-A tumors that were gross-totally resected, it had limited impact in patients harboring PF-EPN-A ependymoma with a sub-total resection[5]. In the same vein, current clinical trial cohorts that are addressing important questions related to other modalities such as the role of chemotherapy (United States - ACNS0831) need to be analyzed in the context of molecular subgroup.…”