Purpose/Objective(s) Recurrent IDH-mutant (IDHmt) gliomas after chemoradiotherapy lack effective salvage therapies and may be selectively reirradiated. Temporally modulated pulsed radiation therapy (TMPRT) is a novel technique that splits the standard daily fraction into multiple low-dose pulses with timed intervals to create a lower effective dose rate. In retrospective studies, TMPRT for re-irradiating recurrent brain tumors was feasible. This prospective trial aims to assess the safety and quality of life (QOL) impact of TMPRT in recurrent IDHmt gliomas. Materials/Methods Patients with recurrent IDHmt gliomas after prior radiation therapy (RT) received 54 Gy at 2 Gy/day, with each fraction administered in 10 pulses of 0.2 Gy at 3-minute intervals. Gross tumor volume (GTV) encompassed both the T1-enhancing and T2 abnormality and was then expanded by 0.5 cm and 0.3 cm for clinical target volume (CTV) and planning treatment volume (PTV), respectively. Dose-limiting toxicity (DLT) was defined as a grade 3 or higher CNS adverse event (AE) at least possibly related to TMPRT within 3 months, while delayed CNS toxicity (DCT) was grade 3 or higher AE occurring beyond 3 months. Symptoms were recorded at baseline, 3, 6, and 12 months using MD Anderson Symptom Inventory Brain Tumor (MDASI-BT), defining deterioration as >1 point increase. Quality of life (QOL) was assessed using Linear Analog Scale Assessment (LASA), defining deterioration as ≥1 point decrease. A historical cohort of 31 recurrent IDHmt patients reirradiated to a median of 36 Gy (21-54) from 2005-2021 was analyzed for comparison. Results Nine patients (4 oligodendrogliomas and 5 astrocytomas) were enrolled between 7/2022 and 2/2024 with a median follow up of 12.2 months. Median age was 47 years old (34-66), and median time since initial RT was 8.9 years (3.9-29.7). Median prior RT dose was 54 Gy (50.4-60), with 77% of patients having received prior temozolomide or lomustine. Two patients stopped TMPRT early due to DLT (after 44Gy and 48Gy, respectively). Median tumor diameter was 8.2 cm (3.1-10.8), median GTV was 92 cc (13.6-241.8), and median PTV was 256.6 cc (57.2-467.5). Three patients had DLTs, and two had DCTs. All 5 of these patients had tumors > 7 cm, including one with DLT who also had prior grade 3 radiation necrosis (RN) after the initial RT. The 4 remaining patients had tumors ≤ 7 cm and did not experience any severe AEs. At 6 months, 3 patients (33%), who had either DLT or DCT, reported symptom deterioration. Three patients, including one who had DLT, reported QOL deterioration. At one-year, the PFS and OS was 60% and 69%, respectively. The 1-year PFS and OS of the historical cohort of 31 recurrent IDHmt patients were 61% and 71%, respectively. Conclusion DLTs and DCTs were observed after TMPRT for recurrent IDHmt gliomas with diameter > 7 cm. This clinical trial has been amended to restrict future enrollment to tumors ≤ 7 cm and without prior RN.
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