Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies

Jonas E Adolph,Gudrun Fleischhack,Till Milde,Rolf-Dieter Kortmann,Olaf Witt,Torsten Pietsch,Ruth Mikasch,Stefan Rutkowski,Monika Warmuth-Metz,For The German Gpoh Hit-Network ,Stephan Tippelt,Beate Timmermann,Kristian W Pajtler,Ulrich Schüller,Christine Gaab,Martin Mynarek,Brigitte Bison,Stefan Dietzsch,Stefan M Pfister

doi:10.1007/s11060-021-03867-8

Abstract

PurposeSurvival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.MethodsSystemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.ResultsMedian age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.ConclusionNo survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.

Highlights

Recurrent ependymomas (EPN) in children and adolescents feature a poor prognosis, with a median survival after diagnosis of recurrence of only 12 months [1, 2]
To investigate whether chemotherapy was able to extend survival after subtotal resection (STR) or no resection, which normally lead to severely shortened Progression-free survival (PFS) and Overall survival (OS), we considered all relapses with incomplete resections and looked for patients treated with chemotherapy who showed a PFS of at least 12 months after start of chemotherapy
We present a heterogenous cohort of 138 patients with recurrent EPN from two multi-institutional trials and a Germanywide registry

Summary

Introduction

Recurrent ependymomas (EPN) in children and adolescents feature a poor prognosis, with a median survival after diagnosis of recurrence of only 12 months [1, 2]. While survival-benefits for surgery and radiotherapy have been shown in multiple cohorts of recurrent EPN, results on chemotherapy were less favorable [1, 5,6,7,8]. With advances in molecular characterization emerging in recent years, molecularly defined types of EPN are increasingly treated as distinct diseases, with the infratentorial PF-A and supratentorial ZFTA subtype being the most aggressive and most abundant in recurrences [11,12,13]. Most trials on chemotherapy in recurrent EPN were done prior to these findings. Results on the efficacy in specific EPN types are still lacking. Recent molecular analyses have suggested that EPN in general may possess features making them especially resistant to chemotherapy [14, 15], pointing towards the importance of finding chemotherapy-regimens that work for EPN

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