The current standard of care for newly diagnosed glioblastoma (GBM) consists of radiotherapy plus concomitant and adjuvant temozolomide (TMZ), designed as STUPP protocol [1] in 2005. A known long-term complication of this brain radiotherapy is Radiation-Induced Leukoencephalopathy (RIL) [2], defined by the development of diffuse FLAIR-hypersignals and cortico-subcortical atrophy at MRI. It is often associated with clinical symptoms such as subcortical frontal decline, gait apraxia and urinary incontinence, typically manifesting years after GBM treatment in long survivors [3], [4]. Since RIL is irreversible and can result in severe disability, preventing its onset is crucial. Moreover, identifying patients at higher risk may lead to potential adjustments to treatment regimen or closer monitoring.

While RIL is generally considered a late-onset complication, some patients develop both radiologically and clinical features of RIL in a short delay (within 6 months) after STUPP protocol completion. This raises the possibility of individual sensitivity to concomitant radio-chemo association. In 2021, a study by Terziev et al. [4] has identified, in a retrospective study, multiple risk factors for RIL, including age at irradiation, smoking, and the PPARγ germline SNP rs2120825.

The ASTER protocol, published in 2019 in the European Journal of Cancer [5], aimed to evaluate the impact of angiotensin II receptor blockers on steroid requirements in GBM patients undergoing radiotherapy (RT). This prospective, multicentric, randomized, double-blinded and placebo-controlled phase III trial included patients according to the following criteria: age of 18 years and older, newly diagnosed GBM (World Health Organization grade 4), Karnofsky performance status (KPS) above 50% and eligibility for standard radiotherapy with concomitant temozolomide treatment, with radiotherapy starting within 10 weeks after surgery. In this study Losartan administration did not reduce steroid requirements in newly diagnosed GBM patients treated with concomitant RT and TMZ.

The main objective of our ancillary study is to retrospectively analyse data from ASTER trial, which used highly controlled and reproducible radiotherapy dosimetry, to identify the incidence of early-onset RIL (within 6 months). As secondary objective, we also aim to explore whether known risk factors, as well as the administration of Losartan – a PPARγ agonist – are associated with a reduced incidence of early-onset RIL.