ANGI-14UPDATE ON A METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY FOR RECURRENT MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR

Abstract

BACKGROUND: Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 22 patients with recurrent medulloblastoma and ATRT treated with an antiangiogenic combination therapy. METHODS: From 11/2006 to 04/2015, 22 patients were diagnosed with recurrent embryonal tumors, 15 with a recurrent medulloblastoma (9 first, 6 multiple recurrences) and seven with recurrent ATRT (4 first, 3 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Median age at start of antiangiogenic therapy was 13 (1-24) years for medulloblastoma and 4 (1-13) years for ATRT. RESULTS: As of 06/2015, 6/15 patients with medulloblastoma are in CR at a median of 63 (9 to 80) months after their last recurrence, one has a partial remission after 6 months, one is stable after 7 months and one is too early to be evaluated. Four patients are off therapy for 62, 45, 41 and 20 months. 5-year-OS is 57.9 ± 14.7% and 5-year-EFS is 39.2 ± 14.9%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy. 3/7 patients with ATRT are in CR, one in PR. Follow-up since last recurrence is 53, 45, 9 and 7 months, two are off therapy for 38 and 34 months. Therapy was generally well tolerated and toxicities were manageable. CONCLUSION: The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.