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

Abstract

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.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Survival of EPN_PFA and EPN_PFB stratified by age. (A) Progression-free survival (PFS) and (B) overall survival (OS) of EPN_PFA stratified by age greater than or less than 10 years. (C) PFS and (D) OS of EPN_PFB stratified by age greater than or less than 18 years. P values determined using log-rank test.

Fig 2.

(A, C, E, and G) Progression-free survival (PFS) and (B, D, F, and H) overall survival (OS) of EPN_PFA stratified by extent of resection across all four cohorts. CERN, Collaborative Ependymoma Research Network; GENE, Global Ependymoma Network of Excellence; GTR, gross total resection; STR, subtotal resection (> 5 mm residual disease). P values determined using log-rank test.

Fig 3.

Value of adjuvant post-operative first-line external-beam irradiation (XRT) in EPN_PFB. (A) Progression-free survival (PFS) and (B) overall survival (OS) of EPN_PFB across the Global Ependymoma Network of Excellence, St Jude’s, and Collaborative Ependymoma Research Network cohorts. (C) PFS and (D) OS of EPN_PFB across the Burdenko cohort. P values determined using log-rank test.

Fig 4.

Nomogram of (A) progression-free survival (PFS) and (B) overall survival (OS) of posterior fossa ependymoma based on the multivariable Cox proportional hazards model. Each effect is translated into a risk score. The individual risk scores need to be totaled by the reader. The score sum can be translated into predicted 5- and 10-year PFS and OS probabilities. EOR, extent of resection; F, female; GTR, gross total resection; M, male; STR, subtotal resection.

Fig A1.

(A-D) Boxplots of the age distribution of EPN_PFA and EPN_PFB, where boxes represent median and interquartile range and whiskers represent 95% CIs. (E) Proportion of patients with EPN_PFA and EPN_PFB in each age group. CERN, Collaborative Ependymoma Research Network; GENE, Global Ependymoma Network of Excellence.

Fig A2.

Forest plots of EPN_PFA versus EPN_PFB across all cohorts and each cohort individually as a univariate analysis, age-adjusted univariate analysis, and multivariable analysis for (A) progression-free survival (PFS) and (B) overall survival (OS). CERN, Collaborative Ependymoma Research Network; GENE, Global Ependymoma Network of Excellence.

Fig A3.

Plot of age at diagnosis as a function of the log10 of the hazard ratios of EPN_PFA versus EPN_PFB for (A) progression-free survival (PFS) and (B) overall survival (OS).

Fig A4.

Survival by subgroup in patients with an age at diagnosis of greater than 10 years for (A) progression-free survival (PFS) and (B) overall survival (OS).

Fig A5.

Sex as a function of extent of resection in EPN_PFA for (A) progression-free survival (PFS) and (B) overall survival (OS). P values were determined using the log-rank test. GTR, gross total resection; STR, subtotal resection.

Fig A6.

Overall survival (OS) of EPN_PFA for the four cohorts divided by (A, C, and E) gross total resection (GTR) and (B, D, and F) subtotal resection (STR). P values were determined using the log-rank test. CERN, Collaborative Ependymoma Research Network; GENE, Global Ependymoma Network of Excellence; XRT, radiotherapy.

Fig A7.

Progression-free survival (PFS) and overall survival (OS) EPN_PFB stratified by extent of resection for (A and B) the combined Global Ependymoma Network of Excellence (GENE), St Jude’s, and Collaborative Ependymoma Research Network (CERN) cohorts and (C and D) the Burdenko Cohort. GTR, gross total resection; STR, subtotal resection.