Clinical Summary:

• Design/Population: A single-arm, phase 2 trial evaluated radiotherapy plus temozolomide and fluoxetine in newly diagnosed patients with grade 4 glioma.
• Key Outcomes: The combination appeared feasible and tolerable, with manageable toxicity and a potential signal of progression-free survival benefit.
• Clinical Relevance: Fluoxetine added to standard chemoradiotherapy may represent a promising investigational strategy in newly diagnosed grade 4 glioma, but longer follow-up and larger studies are needed to confirm efficacy and safety.

Results from a phase 2 study suggest that the addition of fluoxetine to standard chemoradiotherapy was feasible and had manageable toxicity among newly diagnosed patients with grade 4 glioma.

“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,” stated Zhigang Liu, MD, PhD, Dongguan People's Hospital, Dongguan, China, and coauthors. “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.”

In this single-arm study, 27 patients received 60 Gy in 30 fractions of radiotherapy concurrently with 75 mg/m² of once daily temozolomide and 20 mg of once daily fluoxetine (escalated to 40 mg after 1 week). Following chemoradiotherapy, patients received 6 cycles of adjuvant temozolomide at 150 to 200 mg/m²/day for 5 days every 28 days and continued 40 mg/day fluoxetine for 6 months. The primary end point was 1-year progression-free survival (PFS). A key secondary end point was safety. 

At analysis, 17 patients had completed at least 1 year of follow-up or experienced disease progression and were evaluable for efficacy. The 1-year PFS rate was 52.9%. The most common adverse events included alopecia (100%), nausea (41.2%), insomnia (23.5%), and seizures (17.6%), all of which were grade 1/2.  Grade 3 elevated aminotransferase was reported in 1 patient. 

“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,” concluded Dr Liu.

Source:

Liu Z, Jiang L, Wang Z, et al. Radiotherapy combined with temozolomide and fluoxetine for newly diagnosed grade 4 glioma: Preliminary report from a single-arm, prospective phase II clinical trial. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract e14073.