Re-irradiation for malignant glioma: Toward patient selection and defining treatment parameters for salvage

Abstract

PurposeReirradiation for recurrent glioma remains controversial without knowledge of optimal patient selection, dose, fractionation, and normal tissue tolerances. We retrospectively evaluated outcomes and toxicity after conventionally fractionated reirradiation for recurrent high-grade glioma, along with the impact of concurrent chemotherapy.Methods and materialsWe conducted a retrospective review of patients reirradiated for high-grade glioma recurrence between 2007 and 2016 (including patients with initial low-grade glioma). Outcome metrics included overall survival (OS), prognostic factors for survival, and treatment-related toxicity.ResultsPatients (n = 118; median age 47 years; median Karnofsky performance status score: 80) were re-treated at a median of 28 months (range, 5-214 months) after initial radiation therapy. The median reirradiation dose was 41.4 Gy (range, 12.6-54.0 Gy) to a median lesion volume of 202 cm3 (range, 20-901 cm3). The median cumulative (initial radiation and reirradiation combined) potential maximum brainstem dose was 76.9 Gy (range, 5.0-108.3 Gy) and optic apparatus dose was 56.0 Gy (range, 4.5-90.9 Gy). Of the patients, 56% received concurrent temozolomide, 14%, bevacizumab, and 11%, temozolomide plus bevacizumab; 19% had no chemotherapy. The planned reirradiation was completed by 90% of patients. Median OS from the completion of reirradiation was 9.6 months (95% confidence interval [CI], 7.5-11.7 months) for all patients and 14.0, 11.5, and 6.7 months for patients with initial grade 2, 3, and 4 glioma, respectively. On multivariate analysis, better OS was observed with a >24-month interval between radiation treatments (hazard ratio [HR]: 0.3; 95% CI, 0.2-0.5; P < .001), reirradiation dose >41.4 Gy (HR: 0.6; 95% CI, 0.4-0.9; P = .03), and gross total resection before reirradiation (HR: 0.6, 95% CI, 0.3-0.9; P = .02). Radiation necrosis and grade ≥3 late neurotoxicity were both minimal (<5%). No symptomatic persistent brainstem or optic nerve/chiasm injury was identified.ConclusionsSalvage reirradiation, even at doses >41.4 Gy in conventional fractionation, along with chemotherapy, was safe and well tolerated with meaningful survival duration. These data provide information that may be useful in implementing safe reirradiation treatments for appropriately selected patients and guiding future studies to define optimal reirradiation doses, maximal safe doses to critical structures, and the role of systemic therapy.

3D Conformal Re-Irradiation with Temozolamide for Recurrent Glioblastoma: A Prospective Cohort Study

“…The authors reported that there is no symptomatic persistant brain stem or optic chiasma injury. Grade ≥ 3 late toxicity and radiation necrosis were minimal (less than 5%) [31].…”

“…They observed 60% progression-free survival in 6 months. Another prospective study using 4 -6 cycles temozolamide followed by re-irradiation with 3D conformal radiotherapy (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) in recurrent high-grade glioma (grade III and IV). Overall response rate was 20.6% and stable disease was 45% [30].…”

Appraisal of re-irradiation for the recurrent glioblastoma in the era of MGMT promotor methylation

“…With conventional fractionated re-RT and median cumulative EQD2 of 99.3 Gy, symptomatic persistent brainstem or optic nerve/chiasm injury was not observed at median cumulative brainstem dose of 76.9 Gy (5.0–108.3 Gy) and optic apparatus dose of 56.0 Gy (4.5–90.9 Gy) [27]. Late CNS toxicity, radiation necrosis, and short-term steroid requirement were not significantly affected by re-RT volume, maximum brainstem/optic structure dose, or time interval of re-RT.…”

“…In a study of 118 patients with recurrent malignant glioma (GBL in 74%) treated with CFRT (12.6–54 Gy) with daily dose of 1.8 Gy plus TMZ at 28 months after initial RT, the median OS of 9.6 months was significantly better with dose >41.4 Gy (12.4 vs. 7.1 months) and gross total resection before re-RT (11.9 vs. 7.7 months). The radionecrosis chance was <5% [27]. Another study has found an improvement of median OS by combining re-RT with unspecified chemotherapeutic agents (12.2 vs. 8.2 month) [6].…”

Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial

“…Although historically repeat fractionated radiation for gliomas was considered prohibitively toxic, modern radiation techniques allow for repeat radiation in many cases [8][9][10][11][12][13][14]. Several studies have directly assessed fractionated reirradiation with concomitant bevacizumab and have demonstrated its safety [15][16][17][18].…”