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Hypofractionated stereotactic radiotherapy (HSRT) with higher per-fraction doses improved overall response rate (ORR) and progression-free survival (PFS) compared with a lower-dose regimen in patients with recurrent high-grade glioma (HGG).

Specifically, HSRT delivered as 27 Gy in three fractions or 30 Gy in five fractions improved ORR compared with 35 Gy in 10 fractions among patients receiving concurrent bevacizumab in a phase 2 trial. Feng Liu, MD, presented these new findings of the study at the American Society for Radiation Oncology (ASTRO) 2025 Annual Meeting in San Francisco. Liu is the director of head and neck radiotherapy at Hunan Cancer Hospital in Changsha, China.

At 6 months, ORR was 79% and 74% for the 27 Gy and 30 Gy regimens, respectively, compared with 50% for the 35 Gy regimen (P = .023). Six-month PFS was 68% and 62% for the 27 Gy and 30 Gy regimens, respectively, compared with 47.1% for the 35 Gy regimen (P = .023). Overall survival was similar across arms — 85.3%, 79.4%, and 76.5% for the 27 Gy, 30 Gy, and 35 Gy regimens, respectively (P = .81).

Gliomas are the most prevalent primary malignancies of the central nervous system, and HGGs (World Health Organization [WHO] grades 3 and 4) have a high rate of recurrence and poor prognosis.

“The combination of hypofractionated stereotactic radiotherapy and bevacizumab represents a promising treatment strategy for recurrent HGG. However, the optimal dose-fractionation pattern remains undefined,” Liu said. The regimens most commonly used in clinical practice are 27 Gy in three fractions, 30 Gy in five fractions, and 35 Gy in 10 fractions. No randomized trials have directly compared their efficacy, Liu noted.

Study Methods

In this phase 2 trial, investigators evaluated the efficacy and toxicity of each regimen given with concurrent bevacizumab. Adults with pathologically confirmed WHO grade 3-4 gliomas and unequivocal imaging evidence of progression within 21 days of enrollment were eligible. Tumor size could not exceed 3.5 cm. Patients received bevacizumab (10 mg/kg every 2 weeks), starting on day 1 of HSRT and continuing until progression.

The primary endpoint was ORR; secondary endpoints included PFS, overall survival at 6 months, and treatment-related toxicity. MRI was performed at 4 and 8 weeks after HSRT and every 3 months thereafter until progression or death, with evaluation by modified Response Assessment in Neuro-Oncology (RANO) criteria, Liu said in an interview with Medscape Medical News.

A total of 102 patients were randomized (34 per group). About 40% and 60% had grade 3 and grade 4 disease, respectively.

Adverse Events

Grade 1-2 adverse events occurred more frequently with the 27 Gy and 30 Gy regimens (47.1% and 44.1%) than with 35 Gy (17.6%). The most common were headache, nausea/vomiting, insomnia, alopecia, anorexia, and fatigue. Differences between the 27 Gy and 30 Gy regimens were not significant. Rates of grade 3-4 adverse events were comparable across groups: 29.4%, 32.3%, and 20.6% for the 27 Gy, 30 Gy, and 35 Gy regimens, respectively.

Multivariate analysis identified HSRT dose-fractionation, tumor grade, isocitrate dehydrogenase mutation, and 1p/19q codeletion status as significant predictors of PFS.

Limitations and Next Steps

Bevacizumab, a monoclonal antibody targeting VEGF, is often added to reirradiation for recurrent glioblastoma. This drug helps reduce symptomatic radiation necrosis and other radiation-related adverse effects, said Rupesh Kotecha, MD, chief of radiosurgery and director of the Central Nervous System Metastasis Program at Baptist Health Miami Cancer Institute, Miami.

The trial used modified RANO criteria to help distinguish true treatment response from the vascular effects seen with therapies such as bevacizumab. These vascular effects can make MRI results appear more favorable than the underlying disease. While the modified RANO criteria improve response assessment in patients treated with anti-VEGF therapy, additional literature suggests that these criteria don’t entirely eliminate the interpretive challenges posed by bevacizumab-related imaging changes.

“Although overall response rates and progression-free survival estimates appeared higher in the three- and five-fraction cohorts, all patients received concurrent and adjuvant bevacizumab. Given bevacizumab’s known effect on vascular permeability and contrast enhancement, radiographic response does not reliably reflect true changes in tumor burden, limiting the interpretability of ORR in this setting,” Kotecha told Medscape Medical News.

“Despite this limitation, the findings reinforce the feasibility of hypofractionated reirradiation regimens (3-5 fractions) for well-selected patients, consistent with forthcoming consensus guidelines from the International Stereotactic Radiosurgery Society (ISRS). Future investigations should incorporate advanced imaging biomarkers to better delineate biologically active tumor regions and enable higher-precision targeting, particularly when using more hypofractionated approaches,” Kotecha said.

Both Liu and Kotecha reported having no relevant disclosures.