Low Dose Fractionated Radiation Therapy as a ChemoPotentiator of Salvage Temozolomide (TMZ) for Recurrent Anaplastic Astrocytoma (AA) and Glioblastoma Multiforme (GBM): A Single-Arm Phase I/II Trial

Cell survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety and efficacy of low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator of concurrent TMZ for patients with recurrent GBM or AA.Patients with recurrent GBM or AA s/p standard of care therapy and ≥12 months from prior RT and ≥2 months from prior TMZ were eligible to receive 0.5 Gy of RT twice daily for 10 fx with concurrent TMZ (150-200 mg/m2), both delivered in 5 consecutive days of a 28-day cycle for up to 6 cycles, followed by 6 more cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after starting therapy. Brain MRIs were obtained every 2 months, or every 1 month in cases of potential progression. Progression was defined by RANO criteria. Pseudoprogression consisted of MRI changes independent of clinical deterioration or steroid use that stabilize/reverse without oncologic intervention. The primary endpoint was 1-year overall survival (OS), with a lower bound of an 80% CI >28% deemed promising for further study based on historical data. Secondary endpoints were rates of pseudoprogression and hematologic toxicity.Thirty-one patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was seen in 8 (27%) patients. Median follow-up was 9.5 (range: 0.1-66.3) months (mos). Median and 1-yr OS were 9.6 (95% CI = 7.0-15.4) mos and 34.5% (95% CI = 20.9%-57.0%). The lower bound of the 80% CI for 1-yr OS was 24.8%. 77% of patients experienced pseudoprogression, with a median time to pseudoprogression from start of LDFRT of 1.9 (95% CI = 1.7-4.4) mos and median duration of 3.6 (95% CI = 1.6-Not estimable) mos. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 mos, HR = 0.12 [95% CI = 0.03-0.40]; P < 0.01).LDFRT in the re-irradiation setting for GBM or AA was safe. High rates of pseudoprogression were observed at strikingly low RT doses, with improved OS amongst patients with vs. without pseudoprogression. While pseudoprogression is common at definitive doses of brain RT, it is rare at palliative doses (e.g., 30 Gy/10 fx). Thus, low-dose RT hypersensitivity may be elicited by LDFRT with TMZ for patients with GBM/AA. Further study is needed to optimally apply this radiobiological property to improve patient outcomes.