Final results of the prospective phase 2 marcie trial: efficacy and toxicity of postoperative bimodal radiotherapy with c12-boost in patients with atypical meningiomas following subtotal resection

Abstract Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.