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Clinical Trial
. 2025 Oct 1;27(10):2726-2737.
doi: 10.1093/neuonc/noaf132.

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  1 , Sarah E S Leary  2 , Guolian Kang  3 , Bryan K Li  4 , Stewart Kellie  5 , Laura Hayes  6 , Dennis Shaw  7 , Ben Ho  4 , Alyssa Reddy  8 , Jeffrey Gossett  3 , Peter C Burger  9 , Alexander R Judkins  10 , Paul Aridgides  11 , J Russell Geyer  2 , Amar Gajjar  12 , Ian F Pollack  13 , Maryam Fouladi  14 , Annie Huang  4
Affiliations
Clinical Trial

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 et al. Neuro Oncol. .

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.

Keywords: embryonal tumor with multilayered rosettes; medulloblastoma; methotrexate; pediatric brain tumor; pineoblastoma.

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References

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