A combined analysis of two randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma

Abstract

BACKGROUND The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Stupp protocol uses 6 months, however, in routine care, it is often extended to 12 months, given its tolerability, lack of effective salvage treatments, and extended regimen in lower grade gliomas.

METHODS GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled patients with newly diagnosed glioblastoma without progression at the end of 6 months post-radiation temozolomide. Participants were randomised in a 1:1 allocation to either six additional months (total 12 months) or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required for 80% power to detect an improvement in 6mPFS from 50% to 60%. Neither study recruited sufficient patients, so we performed a combined analysis of individual patient data.

RESULTS 205 patients were recruited: 169 in GEINO14-01 (2014–2018) and 46 in EX-TEM (2019–2022). Median follow up was 20 and 14.5 months respectively. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR 0.75, p = 0.4), nor across any subgroups including MGMT methylated. There was no significant improvement in PFS (HR 0.92, P = 0.59, median 7.8 vs 9.7 months) or OS (HR 1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required changes to treatment, with 4.5% requiring dose delay, 7.5% dose reduction and 1.5% discontinuation of temozolomide.

CONCLUSION For patients with newly diagnosed glioblastoma, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any individual patient subset that appeared to benefit from extended treatment. Six months should remain standard of care.