Previously, results from the photon cohort of the NRG-BN001, a signal seeking Phase II randomized trial, indicated that photon radiation dose intensification (75 Gy) did not demonstrate improvement in overall survival (OS) for patients with newly diagnosed glioblastoma (GBM). The recent analysis of the proton cohort revealed improved survival for patients receiving proton therapy at 75 Gy. Because this data met the pre-defined survival improvement threshold, they could be used to design and conduct a definitive phase III randomized trial. These results were recently reported at the American Society for Radiation Oncology Annual Meeting in San Francisco, California.
We had developed this trial to test the potential survival advantage using proton therapy combined with temozolomide for GBM with the dual hypothesis of the benefit of dose-escalation and the sparing effect on lymphocytes in circulation, critical in maintaining an anti-tumor immune response, and are excited to report that the predefined signal to support the development of a definitive Phase III trial of proton dose-escalation for GBM has been achieved."
Minesh P. Mehta, MD, with Baptist Health Miami Cancer Institute and Florida International University Herbert Wertheim College of Medicine and lead author of the NRG-BN001 abstract
Data from prior single-arm, non-randomized studies utilizing temozolomide established simultaneous integrated boost (SIB) radiation therapy dose intensification to 75 Gy as safe and effective in patients with GBM. NRG-BN001 was designed as a phase II study testing the hypothesis that this dose intensified regimen could be potentially as or more effective in treating patients with GBM. Additionally, lymphopenia is commonly associated with the low dose region commonly encountered with photon radiotherapy and has been demonstrated to have dose-volume dependency, and a survival decrement with lymphopenia in GBM has been established. Proton therapy has been demonstrated to decrease the occurrence of acute severe lymphopenia, suggesting a potential biologic mechanism of benefit for GBM patients. NRG-BN001 addressed both hypotheses comparing 75 Gy intensity modulated radiation therapy (IMRT) and 75 Gy proton therapy to standard of care 60 Gy radiation therapy.
The proton therapy cohort of NRG-BN001 included 193 evaluable patients. The proton therapy arm demonstrated improved OS (HR= 0.81, 70% CI 0.67-0.98, p =0.11 (prespecified type I error of 0.15)) and the improvement in survival remained significant when correcting for MGMT methylation status and recursive partitioning analysis (RPA) class. The absolute survival improvement in favor of the proton therapy arm at 2 and 3 years was 6.8% (43.1 vs 49.9%) and 4.6% (25.4 vs 30%). As expected, OS was superior for both MGMT methylated as well as for lower recursive partitioning analysis (RPA) class patients, and without significant interaction between treatment arm and either MGMT status or RPA. There was no statistically significant difference in high grade toxicities between treatment arms. Specifically, ≥G3 lymphopenia and ≥G4 neurologic toxicity rates for 60 Gy vs. 75 Gy proton therapy were 23.4 vs 17.1 (absolute difference of 6.3%), and 5 vs 1.8% (absolute difference of 3.2%).
Further research needs to be conducted in a phase III trial setting to determine the full potential benefit for proton therapy in this patient population.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U10CA180868 (NRG Oncology Operations), UG1CA189867 (NCORP), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Specimen Bank), U24CA180803 (IROC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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