Resection and radiotherapy for intracranial ependymoma: a multiinstitutional 50-year experience

OBJECTIVE Maximal safe resection is the standard-of-care treatment for adults with intracranial ependymoma. The value of adjuvant radiotherapy remains unclear as these tumors are rare and current data are limited to a few retrospective cohort studies. In this study, the authors assembled a cohort of patients across multiple international institutions to assess the utility of adjuvant radiotherapy in this patient population. METHODS Adults with intracranial ependymoma managed surgically at the University Health Network in Toronto, Canada, the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma, and The Ottawa Hospital in Ottawa, Canada, were included in this study. The primary end points were progression-free survival (PFS) and overall survival (OS). Clinicopathological variables were assessed in univariate and multivariate Cox proportional hazard models for prognostic significance of PFS and OS. RESULTS A total of 122 patients diagnosed between 1968 and 2019 were identified for inclusion. The majority of patients had grade II ependymomas on histopathology (78%) that were infratentorially located (71%), underwent gross-total (GTR) or near-total resection (NTR; 55%), and were treated with adjuvant radiotherapy (67%). A volumetric analysis of the extent of resection in 49 patients with available tumor volume data supported the accuracy of the categorical GTR, NTR, and subtotal resection (STR) groups utilized. Independent statistically significant predictors of poorer PFS in the multivariate analysis included STR or biopsy (vs GTR/NTR; HR 5.4, 95% confidence interval [CI] 2.4–11.0, p < 0.0001) and not receiving adjuvant radiotherapy; cranial (HR 0.5, 95% CI 0.2–1.1) and craniospinal (HR 0.2, 95% CI 0.04–0.5) adjuvant radiotherapy regimens improved PFS (p = 0.0147). Predictors of poorer OS in the multivariate analysis were grade III histopathology (vs grade II: HR 5.7, 95% CI 1.6–20.2, p = 0.0064) and undergoing a biopsy/STR (vs GTR/NTR: HR 9.8, 95% CI 3.2–30.1, p = 0.0001). CONCLUSIONS The results of this 50-year experience in treating adult intracranial ependymomas confirm an important role for maximal safe resection (ideally GTR or NTR) and demonstrate that adjuvant radiotherapy improves PFS. This work will guide future studies as testing for molecular ependymoma alterations become incorporated into routine clinical practice.

P.130 Clinical prognostic factors in adult intracranial ependymoma patients – A fifty year multi-institutional experience

Background: Standard of care treatment for adult intracranial ependymoma patients includes maximal safe surgical resection, while the role for adjuvant radiotherapy remains unclear with existing data from small retrospective series’. Accordingly, we built a multi-institutional cohort to assess the prognostic value of adjuvant radiotherapy and other clinical factors in these patients. Methods: Patients managed for adult intracranial ependymomas from 1968 onwards within the University Health Network in Toronto, The University of Oklahoma Health Sciences Center, and The Ottawa Hospital were identified. Multivariate models assessing the prognostic value of clinical factors were built using variables with known prognostic value and/or significance in univariate Cox models. Results: Of 122 ependymomas, 71% were infratentorial, 78% grade two, 55% gross/near-totally resected (GTR/NTR), and 65% treated with adjuvant radiotherapy. Multivariate analyses identified GTR/NTR (vs. subtotal resection; HR=0.2, 95%CI=0.1–0.4, p<0.0001) and cranial (HR=0.5, 95%CI=0.2–1.1) or craniospinal (HR=0.2, 95%CI=0.04–0.5) radiotherapy receipt (p=0.01) as independent statistically significant predictors of more favourable PFS. Grade II pathology (vs. grade III; HR=0.2, 95%CI=0.05–0.6, p=0.006) and GTR/NTR (vs. subtotal resection; HR=0.1, 95%CI=0.03–0.3, p=0.0001) were independent statistically significant predictors of better OS. Conclusions: This work confirms the importance of maximal safe resection for adult intracranial ependymomas and establishes that adjuvant radiotherapy improves progression-free survival in these patients.

Treatment and outcome of intracranial ependymoma after first relapse in AIEOP 2 nd protocol

Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2 nd AIEOP protocol. Methods We considered relapse sites and treatments ,i.e. various combinations of complete/incomplete surgery, if followed by standard or hypo-fractionated radiation(RT) ± chemotherapy(CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse(LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well posed, randomized questions could clarify the numerous issues, orient salvage treatment and ameliorate prognosis for this group of patients.

EPEN-04. SIOP EPENDYMOMA I: FINAL RESULTS, LONG TERM FOLLOW-UP AND MOLECULAR ANALYSIS OF THE TRIAL COHORT: A BIOMECA CONSORTIUM STUDY

Introduction Surgery and radiotherapy are established childhood ependymoma treatments. The efficacy of chemotherapy has been debated. We report final results of the SIOP Ependymoma I trial, with 12-year follow-up, in the context of a post-hoc analysis of more recently described biomarkers. Aims and Methods The trial assessed event free (EFS) and overall survival (OS) of patients aged three to 21 years with non-metastatic intracranial ependymoma, treated with a staged management strategy targeting maximum local control. The study also assessed: the response rate (RR) of subtotally resected (STR) disease to vincristine, etoposide and cyclophosphamide (VEC); and surgical operability. Children with gross total resection (GTR) received radiotherapy of 54 Gy in 30 daily fractions over six weeks, whilst those with STR received VEC before radiotherapy. We retrospectively assessed methylation and 1q status alongside hTERT, RELA, Tenascin C, H3K27me3 and pAKT expression. Results Between 1999 and 2007, 89 participants were enrolled, 15 were excluded with metastatic (n=4) or non-ependymoma tumours (n=11) leaving a final cohort of 74. Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. 1q gain was associated with poorer EFS (p=0.002, HR=3.00, 95%CI 1.49–6.10). hTERT expression was associated with worse five-year EFS (20.0% Vs 83.3%, p=0.014, HR=5.8). GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.006, HR=2.81, 95% confidence interval 1.35–5.84). There was an improvement in GTR rates in the latter half of the trial (1999-2002 32.4% versus 2003-2007 56.8%). Despite the protocol, 12 participants with STR did not receive chemotherapy. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1). Conclusions VEC exceeded the pre-specified RR of 45% in children over three years with STR intracranial ependymoma. However, cases of inaccurate stratification at treating centres highlights the need for rapid central review. We also confirmed associations between 1q gain, hTERT expression and outcome.

EPEN-01. MULTIDISCIPLINARY TREATMENT IN EPENDYMOMA

BACKGROUND In intracranial ependymoma, the effectiveness of chemotherapy and radiation therapy is unclear, and the degree of tumor removal contributes to the improvement of life prognosis. METHODS We examined ependymoma cases treated in our institution from July 1998 to March 2017. RESULTS There were 18 boys and 7 girls. The average age at the time of surgery is 5.3±3.6 years. The pathological diagnosis was Grade II for 8 cases and Grade III for 17 cases. Genetic analysis was performed in 16/25 cases (64%). Of the infratentorial cases, 10/11 cases (90.1%) were PFA and PFB were one case. Of the supratentorial cases, 3/5 cases (60%) were positive for RELA fusion. As chemotherapy, 19 patients were VCR + VP-16 + CDDP + CPA. Irradiation was performed in all cases, local irradiation (50.4–55.8Gy) in 22 cases (88%), and craniospinal irradiation in 2 cases (8%). The 7-year OS was 74.6±9% and the 7-year PFS was 59.7±10.5%. Grade III showed a short OS (p = 0.053). GTR and NTR were obtained in the first excision in 14 cases (56%), and OS and PFS were not significantly different from those in the STR group (p = 0.219, p = 0.248). GTR and NTR including 2nd-look surgery were obtained in 18 cases (72%), and significant improvement of OS was observed compared with STR group (p = 0.02). CONCLUSION Even if it is not GTR or NTR at the first operation, improvement of OS is expected by total excision after chemotherapy.

RONC-16. PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL EPENDYMOMA UNDER 3 YEARS OLD: INITIAL CLINICAL OUTCOMES

BACKGROUND Proton beam therapy (PBT) provides dosimetric benefits in sparing normal tissue when treating pediatric patients with brain tumors. We report the preliminary clinical outcomes of surgery and adjuvant PBT for patients under 3 years old diagnosed as intracranial ependymoma at our institute. METHODS This is a retrospective review of the medical records for 3 children with ependymoma in the fourth ventricle, diagnosed between March 2013 and September 2019. PBT was performed after tumor resection in all the patients. RESULTS Gross total resection was achieved in 2 males and 1 female patients with fourth ventricle WHO grade II to III ependymoma at 15, 18, and 37 months old. All the patients received adjuvant PBT (54.0 GyE/30 fractions) to the postoperative tumor bed under general anesthesia or sedation. PBT was acutely well tolerated, with mostly mild alopecia and skin reactions at the irradiated sites. At a median follow-up of 54 months (4–59 months) after irradiation, all the patients are alive without recurrence. No serious late adverse events were observed in any of the patients. CONCLUSION The number of patients in this study remains small for drawing any definite conclusion, however our preliminary results are still encouraging. Further studies of a large number of pediatric patients with long term follow-up are needed to more fully assess tumor control and late adverse events.