Radiotherapy combined with temozolomide and fluoxetine for newly diagnosed grade 4 glioma: Preliminary report from a single-arm, prospective phase II clinical trial.

Abstract

e14073 Background: Grade 4 gliomas, including glioblastoma (GBM), are associated with poor prognosis and limited treatment options, It is common for patients with glioma to experience depression, and some studies have reported a significant association between depression and adverse survival outcomes in malignant glioma. Fluoxetine, initially developed and approved as a selective serotonin reuptake inhibitor (SSRI) for the treatment of depression, has exhibited anti-tumor effects in glioma cells by inducing lysosomal stress. A retrospective study indicated that concomitant chemoradiotherapy combined with fluoxetine significantly extends the survival of patients with GBM. Our study aims to investigate the efficacy and safety of the combination of fluoxetine and temozolomide with radiotherapy for the treatment of newly diagnosed Grade 4 glioma. Methods: This is a single-arm, single-center, prospective phase II clinical trial for patients with newly diagnosed Grade 4 glioma confirmed by surgical pathology or biopsy, was registered on May 20, 2024 in the Chinese Clinical Trial Registry(ChiCTR2400084456 ). Patients receive radiotherapy (60 Gy/30F) with concurrent daily temozolomide (75 mg/m²/day) and fluoxetine (starting at 20 mg/day, increased to 40 mg after 1 week). Following chemoradiation, patients undergo 6 cycles of adjuvant temozolomide (150–200 mg/m²/day for 5 days every 28 days) and continue fluoxetine (40 mg/day) for 6 months. The primary endpoint is 1-year progression-free survival(PFS) rate, and secondary endpoints include overall survival, safety, quality of life score, and cognitive function. Results: From May 20, 2024, to November 10, 2025, a total of 27 patients were successfully enrolled, including 25 cases of glioblastoma and 2 cases of grade 4 astrocytoma. Among the enrolled patients, there are 19 cases with wild-type IDH1/2, 6 cases that were not tested, and 2 cases with an IDH1 mutation. 13/27(48.1%) exhibited depressive tendencies (SDS score > 50) prior to chemoradiotherapy. As of December 31, 2025, a total of 17 patients who had completed one year of follow-up or experienced disease progression were included. The 1-year PFS rate was 52.9% (9/17). The most common adverse reactions included alopecia (17/17, 100%), nausea (7/17, 41.2%), insomnia (4/17, 23.5%), and seizures (3/17, 17.6%), all of which were grade 1-2. Only 1 case (5.9%) experienced a grade 3 adverse reaction, manifested as elevated alanine aminotransferase levels. Conclusions: These preliminary findings suggest that the combination of radiotherapy, temozolomide, and fluoxetine is feasible, has manageable toxicity, and demonstrates potential PFS benefit in patients with newly diagnosed Grade 4 glioma. We will continue to complete the follow-up of this study cohort, and further investigation in larger cohorts is warranted to confirm our results. Clinical trial information: ChiCTR2400084456.