Abstract
BACKGROUND: Since the 2021 WHO CNS tumour classification, IDH-mutant WHO grade 4 astrocytoma has been recognised as a distinct molecular entity, separate from IDH-wildtype glioblastoma. While the Stupp protocol (60 Gy in 30 fractions with concurrent and/or adjuvant temozolomide) is standard for glioblastomas (IDH-wildtype), no single standard exists for IDH-mutant tumours. Some institutions adopt Stupp by analogy; others favour CATNON-based regimens (59.4 Gy in 33 fractions with adjuvant temozolomide). The choice of regimen and number of cycles varies. Evidence to guide treatment remains limited. MATERIAL AND METHODS: We retrospectively reviewed patients with IDH-mutant grade 4 astrocytoma treated with a chemo-radiation approach at two UK neuro-oncology centres from 2019-2024. All underwent maximal safe resection followed by radiotherapy (60 Gy in 30 fractions), with concurrent and, where possible, 6-12 cycles of adjuvant temozolomide. Demographic, molecular, treatment and outcome data were collected. MGMT promoter methylation was assessed quantitatively, with ≥10% considered methylated. Kaplan-Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS), with censoring at last follow-up for those that had not progressed or died. RESULTS: Nineteen patients were included (63% male, median age 37 years). Most underwent debulking or partial resection. MGMT promoter methylation was present in 68%. Median PFS was 20 months (range 6-59) and median OS was 28 months (range 8-68). When stratifying by MGMT status, median PFS for the methylated group was 21 months (6-53), OS 28 months (9-68). For the unmethylated group, PFS was 13.5 months (8-18) and OS 20.5 months (8-35). Fourteen patients (74%) completed at least six cycles of adjuvant temozolomide; others discontinued due to progression. Intention to treat analysis confirms when planned for 6 cycles (11 patients), the PFS is 17 (6-39) and OS is 21 (8-68). For 12 intended cycles (8 patients), the PFS is 23.5 (10-59) and OS is 33.5 (15-59). Results are presented as intention-to-treat; as-treated analysis yielded comparable outcomes. At the time of analysis, 37% had progressed and 21% had died. CONCLUSION: This multi-centre retrospective study adds to the limited real-world evidence for IDH-mutant WHO grade 4 astrocytoma. Survival outcomes in our cohort were encouraging, particularly among patients with MGMT promoter methylation and those receiving extended adjuvant temozolomide. These findings reflect variability in practice and highlight the need for prospective data to define optimal management in this molecular subgroup.