Since 2005, the standard treatment for newly diagnosed glioblastoma involves radiotherapy combined with concomitant and adjuvant temozolomide (TMZ), as per the Stupp protocol. A known long-term complication of radiotherapy is Radiation-Induced Leukoencephalopathy (RIL), characterized by diffuse FLAIR-hyperintensities and cortico-subcortical brain atrophy, often leading to cognitive, balance and urinary impairments. While RIL has been typically described years after treatment in long survivors, there is little information regarding early-onset RIL (< 6 months) and its potential risk factors.

This ancillary study aims to assess the incidence of early-onset RIL in glioblastoma patients treated within the ASTER phase III trial. Additionally, we explored potential risk factors, including genetic susceptibility, and evaluate whether Losartan, a PPARγ agonist, reduces early RIL incidence.

We conducted a retrospective analysis of data from the ASTER trial, a randomized, placebo-controlled phase III study evaluating the effects of Losartan on corticosteroid needs in glioblastoma patients receiving standard radiotherapy with concomitant TMZ. Patients were included if they had MRI scans available at baseline and six months post-treatment, with no evidence of tumor progression. Early-onset RIL was defined as an increase of at least two points on the simplified Scheltens rating scale, with associated cortical-subcortical atrophy. Genetic testing focused on the PPARγ germline SNP rs2120825. Statistical analyses included univariate comparisons of clinical and genetic variables.

Among the 31 patients included, 29% ( n = 9) developed early-onset RIL. No significant associations were found between early RIL and known risk factors such as smoking ( P = 0.43), hypertension ( P = 0.12), age ( P = 0.067), or PPARγ TG polymorphism ( P = 0.68). Similarly, Losartan administration (100 mg/day) showed no significant effect on prevention of early RIL ( P = 0.72). The limited power of the study may explain the lack of significant findings.

This study reports a high incidence (29%) of early-onset RIL in glioblastoma patients treated with the Stupp protocol, highlighting the question of individual sensitivity to this severe side effect. While previous research suggests a role for PPARγ in radiation-induced toxicity, this study was underpowered to confirm whether Losartan, as PPARγ agonist, could offer protection against early-onset RIL. The lack of significant results underscores the need for larger, prospective trials to further investigate these factors and develop targeted preventive strategies.