Among patients with recurrent high-grade glioma, investigators found that fractionated reirradiation is safe and feasible, suggesting higher reirradiation dose may be feasible, according to data from a retrospective study published in Neuro-Oncology Advances.
Among the 230 patients with high-grade glioma reviewed, the median follow-up was 8.8 months and the median reirradiation dose was 41.4 Gy (Gray) with 80.4% of patients receiving concurrent systemic therapy. Moreover, the median cumulative maximum doses to brainstem and optic structures were 77.9 Gy and 55.1 Gy, respectively. No injuries to these structures were identified. Furthermore, the median overall survival (OS) was 10.2 months from reirradiation start, whereas the median OS for patients with IDH wildtype glioblastoma was 8.7 months.
Glossary:
Gy fractions: the division of a total radiation dose (measured in Grays, or Gy) into smaller, individual doses given over time during radiation therapy
Overall survival (OS): the average length of time that patients are alive after being diagnosed with or starting treatment for a disease.
Multivariate analysis: a statistical method that examines the relationships between multiple variables simultaneously.
Radiation necrosis: permanent damage to healthy tissue caused by radiation therapy.
When looking to the multivariate analysis, improved OS was associated with better Karnofsky performance status, longer interval between radiotherapy sessions, reirradiation at first recurrence and reirradiation dose greater than or equal to 41.4 Gy; however, the multivariate analysis of patients with IDH wildtype revealed that improved OS was associated with a longer interval between radiotherapy sessions and higher reirradiation dose.
“These data support the safety and efficacy of fractionated reirradiation for recurrent high-grade glioma. They suggest higher reirradiation dose may be feasible, including for large treatment volumes and for tumors near the brainstem or optic structures,” lead study author, Dr. Michael C. LeCompte, and colleagues wrote in the journal article; he works in the Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, in Baltimore, Maryland.
There is currently no standard-of-care treatment for recurrent high-grade glioma. Although studies suggest that reirradiation, with or without systemic therapy, is associated with survival, questions remain regarding optimal reirradiation target volumes, tumor molecular features that influence treatment response, dose and fractionation strategies, as well as cumulative dose limitations for key intracranial structures.
Based on this unmet need, investigators have offered conventionally fractionated reirradiation at a reduced dose compared with the initial radiotherapy course, based on the hypothesis that this may be safer than hypofractionated regimens, as well as facilitate prolonged systemic therapy and provide a foundation for clinical trials of novel concurrent treatments.
Understanding the Investigation
Eligible patients who were treated at Johns Hopkins University from 2007 to 2022 were evaluated on this retrospective review study. These patients included those who had previously received conventionally fractionated radiotherapy for glioma and later developed recurrent or progressive grade 3 or 4 disease. Patients must have undergone fractionated reirradiation at the institution, with or without prior surgical resection, and have had at least one follow-up visit post-treatment.
All eligible participants underwent fractionated external beam radiotherapy; those treated with stereotactic radiosurgery or stereotactic radiotherapy were excluded from the investigation. Treatment was administered in 1.5 to 3.5-Gy (Gray) fractions, with dose selection based on safety considerations, treatment field overlap and the proximity of critical structures. Moreover, when Temodar (temozolomide) was used, it was given at 75 milligrams per square meter (mg/m2) daily, whereas Avastin (bevacizumab) was administered at 10 mg per kilogram (mg/kg) biweekly. Cumulative doses to the optic apparatus and brainstem were assessed using composite treatment plans or a summation of maximum point doses.
Investigators assessed clinical outcomes such as the date and cause of death, as well as the date of last follow-up. Moreover, radiation-related neurotoxicity such as neurologic side effects at last follow-up, Radiation Therapy Oncology Group (RTOG) acute and late central nervous system (CNS) toxicity, Neofordex (dexamethasone) requirement and radiation necrosis defined by imaging or pathology were all assessed.
A Deeper Look at Results and Safety
At the time of diagnosis, 82.2% of the 230 patients evaluated had a grade 3 or 4 glioma. The median radiation dose was 60 Gy for high-grade glioma and 54 Gy for low-grade glioma. IDH mutation and MGMT promoter methylation status were often unknown in cases treated before 2010 (28.3% and 32.2%, respectively). However, among those with available data, 65.5% were IDH wildtype, and 49.4% (77/156) had MGMT promoter methylation.
Most patients (93%) underwent conventionally fractionated reirradiation with 1.8 to 2 Gy fractions, while others received 2.2 to 3.5 Gy (5.2%) or 1.5 Gy fractions (1.3%). Common fractionation regimens included 45 Gy in 25 fractions (38.3%) and 36 Gy in 20 fractions (22.6%). Reirradiation occurred at first recurrence in 58.2% of cases, with a median interval of 25.9 months from initial treatment (range, 1.6–214.2 months). Sixty percent of patients underwent surgery before reirradiation, including 20.4% with gross total resection and 27.8% with subtotal resection.
When looking at safety, neurotoxicity was minimally observed in patients following reirradiation. Acute grade 3 or higher toxicity occurred in 9.6% of patients, while 70.4% experienced grade 2 toxicity; this was due to the temporary need for steroids during or within three months of treatment. Late grade 3 or higher toxicity was observed in 6.5%, including focal motor weakness (12 cases), aphasia or dysarthria (3 cases), hemineglect (1 case), and urinary incontinence (1 case). Radiation necrosis occurred in 7.8% of all patients and 9.4% of those with post-treatment imaging.
The median time to onset radiation necrosis was 2.1 months. Most cases (83.3%) were diagnosed by imaging alone, while 16.7% were confirmed by pathology. Among necrosis cases, 5.7% were grade 1, 72.2% were grade 2, and 22.2% were grade 3. However, no brainstem radiation necrosis was observed.
“Reirradiation of high-grade glioma using doses of 41.4 to 45 Gy (or 54 Gy in cases of no treatment field overlap), along with the use of concurrent daily [Temodar], appears to be a safe salvage option following a recurrence event,” LeCompte and colleagues concluded. “The current study supports the use of reirradiation doses [greater than or equal to] 41.4 Gy for high grade glioma as well as treatment of large target volumes [greater than or equal to] 200 cm3 as neither were associated with increased risk of treatment-related toxicity, and these may improve OS.”
Reference:
"Fractionated reirradiation of recurrent high-grade gliomas: Safety with higher reirradiation dose and larger targets," by Dr. Michael C. LeCompte, et al. Neuro-Oncology Advances.
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