Phase 3 randomized trial of high-dose methotrexate for young children with high-risk embryonal brain tumors: A report from the Children’s Oncology Group
Claire Mazewski, Sarah Leary, Guolian Kang, Bryan Li, Stewart J. Kellie, Laura L. Hayes, Dennis Shaw, Ben Ho, Alyssa Reddy, Jeffrey M. Gossett, Peter C. Burger, Alexander R. Judkins, Paul Aridgides, J. Russell Geyer, Amar Gajjar, Ian F. Pollack, Maryam Fouladi, Annie Huang
Abstract
BACKGROUND: Embryonal brain tumors are the leading cause of cancer death in young children. METHODS: ACNS0334 was a phase 3 randomized study evaluating high-dose methotrexate in young children < 36 months old with newly diagnosed high-risk embryonal brain tumors. Treatment included 3 cycles of induction chemotherapy with or without methotrexate followed by 3 cycles of high-dose consolidation chemotherapy with hematopoietic stem-cell infusion. Primary endpoint was complete response (CR) at the end of therapy. Secondary endpoints included a comparison of event-free survival (EFS) between arms and to historical controls. Molecular characterization was conducted retrospectively. Tests of significance were one-sided. RESULTS: Of 77 eligible patients, 59 with detectable disease were evaluated for response and 28 (47.5%) achieved CR, 15/30 (50%) treated with methotrexate compared to 13/29 (45%) without methotrexate (P = 0.35). For MB, CR was 12/19 (63%) with methotrexate compared to 6/20 (30%) without methotrexate (P = 0.039). Considering molecular diagnosis, all SHH MB (n = 11) were survivors. Five-year EFS was 70% (90% CI: 39.6-87.2) for 10 Group 3 MB with methotrexate versus 33.3% (90% CI: 15.0-52.9) for 15 without (P = 0.037). In other embryonal tumors, CR was 3/11 (27%) with methotrexate compared to 7/9 (78%) without (P = 0.99). No benefit with methotrexate was observed for Embryonal Tumor with Multilayered Rosettes (n = 14, EFS 20.0% [90% CI: 1.8-52.5] with methotrexate versus 33.3% [90% CI: 10.8-58.1] without, P = 0.58), or pineoblastoma (n = 9, EFS 16.7% [90% CI: 1.6-46.1] with methotrexate versus 0% without, P = 0.52). CONCLUSIONS: The addition of methotrexate to intensive chemotherapy improved CR and EFS for young children with high-risk Group 3 MB, but not other diagnoses.