Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study

TLDR

Children with malignant glioma have a poor prognosis. The study aimed to assess whether adding lomustine to temozolomide after radiotherapy improves event‑free survival in children with anaplastic astrocytoma or glioblastoma and to evaluate the impact of MGMT expression. After maximal resection, patients received involved‑field radiotherapy with concurrent temozolomide, followed by up to six cycles of lomustine and temozolomide every six weeks. Adding lomustine to temozolomide after radiotherapy significantly improved event‑free and overall survival compared with temozolomide alone, with the greatest benefit in patients without gross‑total resection, those with glioblastoma, and those with MGMT overexpression.

Abstract

The prognosis for children with malignant glioma is poor. This study was designed to determine whether lomustine and temozolomide following radiotherapy and concurrent temozolomide improves event-free survival (EFS) compared with historical controls with anaplastic astrocytoma (AA) or glioblastoma (GBM) and whether survival is influenced by the expression of O6-methylguanine-DNA-methyltransferase (MGMT). Following maximal surgical resection, newly diagnosed children with nonmetastatic high-grade glioma underwent involved field radiotherapy with concurrent temozolomide. Adjuvant chemotherapy consisted of up to 6 cycles of lomustine 90 mg/m2 on day 1 and temozolomide 160 mg/m2/day ×5 every 6 weeks. Among the 108 eligible patients with AA or GBM, 1-year EFS was 0.49 (95% CI, 0.39–0.58), similar to the original CCG-945-based design model. However, EFS and OS were significantly improved in ACNS0423 compared with the 86 AA or GBM participants treated with adjuvant temozolomide alone in the recent ACNS0126 study (1-sided log-rank P = .019 and .019, respectively). For example, 3-year EFS was 0.22 (95% CI, 0.14–0.30) in ACNS0423 compared with 0.11 (95% CI, 0.05–0.18) in ACNS0126. Stratifying the comparison by resection extent, the addition of lomustine resulted in significantly better EFS and OS in participants without gross-total resection (P = .019 and .00085 respectively). The difference in EFS and OS was most pronounced for participants with GBM (P = .059 and 0.051, respectively), and those with MGMT overexpression (P = .00036 and .00038, respectively). The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.