International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationInvestigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology/Radiation Therapy Oncology Group Trial 0525
Introduction
Optimal management for recurrent glioblastoma (GBM) has not been established. A plethora of monotherapy and combination therapies have been evaluated. Such approaches include surgery, reirradiation, systematic therapy either with chemotherapy and/or targeted therapeutics or antiangiogenic agents, tumor treatment fields, or some combination of these, as well as supportive care 1, 2, 3, 4, 5, 6. A variety of chemotherapies have been evaluated for recurrent GBM, with modest results. Recently bevacizumab, an antivascular endothelial growth factor monoclonal antibody, was evaluated for recurrent GBM. Phase 2 studies demonstrated favorable 6-month progression-free survival and objective responses with bevacizumab for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM 7, 8, 9, 10. Currently bevacizumab is one of the most commonly used treatment options for patients with recurrent GBM in the United States. On the other hand, for patients with limited volume recurrence, reirradiation seems to provide similar overall survival (OS) in comparison with those treated with bevacizumab 11, 12, 13. Despite some evidence of improvement in progression-free survival, no significant increase in OS has been demonstrated with any particular approach 1, 14. Further investigations are needed to define the optimal choice of salvage therapy, and in particular the role of reirradiation and systemic treatment in patients with recurrent GBM.
Trial RTOG 0525 was a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed GBM (15). Patients were enrolled between January 2006 and June 2008, and primary study findings were published in 2013, where more details of the study design and results can be found (15). All patients received 60 Gy partial-brain irradiation in 2-Gy daily fractions. After progression, patients participating in this trial received variable salvage therapies (reported as nonprotocol therapy). The information on the type of nonprotocol therapy is available for analysis. The purpose of this study was to determine the impact on OS with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in those Trial RTOG 0525 participants. Information from this analysis may help generate new hypotheses for future clinical trials.
Section snippets
Methods and Materials
A total of 833 patients were enrolled and randomized in Trial RTOG 0525. We analyzed postprogression prognosis for patients with information regarding their nonprotocol therapy and excluded patients who died less than half a month after progression (637 analyzable patients), because there would not have been adequate time to consider/evaluate/offer a therapeutic intervention to these patients. The 637 patients were divided into 4 mutually exclusive groups according to the type of nonprotocol
Results
Of the 833 patients who originally enrolled in Trial RTOG 0525, 664 (80%) were recorded to have progression. Salvage management details were available for 660 of 664 of these patients. At the time of this analysis, 563 of 660 participants with disease progression (85%) had died. Of these, 23 died in the first half-month after progression. To focus on patients whose outcomes were most likely affected by salvage therapy, this analysis is restricted to those 637 patients who survived at least half
Discussion
Optimal treatment for patients with recurrent GBM remains a challenge. In the present study we focused on the efficacy of reirradiation and/or systemic treatment as salvage options. Our analysis demonstrated trends toward better survival for patients who received any salvage treatment, either radiation, systemic therapy, or the combination, as compared with those who did not. The median survival of patients who did not receive treatment was only 4.8 months. Patients who received systemic
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This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology Statistics and Data Management Center [SDMC]), and UG1CA189867 (NCI community Oncology Research Program [NCORP]) from the National Cancer Institute, National Cancer Institute of National Institutes of Health under award number R25CA057699 and Merck & Co.
M.P.M.'s current affiliation is Miami Cancer Institute, Coral Gables, Florida.
Conflict of interest: M.P.M. reports consulting fees from BMS, Celldex, Roche, Novartis, Cavion, Varian, Agenus, Insys, and Remedy, consulting fees and grant funding from Novocure, research support from Cellectar, fees from Pharmacyclics (Board of Directors), and Monteris (Data Safety Monitor Board [DSMB]), outside the submitted work. D.T.B. reports honoraria for medical advisory board consultation from Vascular Biogenics, Ltd, outside the submitted work. L.S. reports travel expenses from Varian Medical Systems, outside the submitted work.