International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationInitial Results of a Phase 2 Trial of 18F-DOPA PET-Guided Dose-Escalated Radiation Therapy for Glioblastoma
Introduction
Although previous studies have clearly defined the role of radiation therapy (RT) in delaying progression and improving survival in high-grade gliomas,1 pre–chemotherapy-era dose-escalation (DE) studies with doses up to 90 Gy to regions of magnetic resonance imaging contrast enhancement (MRI-CE) were not successful in improving survival in glioblastoma.2,3 Improved survival associated with temozolomide (TMZ) has led to the re-evaluation of DE as a potential method to improve outcomes,4, 5, 6, 7, 8 as the majority of failures remain in the high-dose (60 Gy) volume.9, 10, 11 The initial results of these reports support a reduction of central recurrences5,12 and improved outcomes; however, these studies were small and could not account for the importance of O6‐methylguanine methyltransferase (MGMT) methylation status as a predictor of outcomes and response to TMZ chemotherapy.13, 14, 15, 16
Previous studies used MRI-CE region to define the DE volume. Since the seminal surgical study by Kelly et al,17, 18, 19 it has been known that tumor can be present in regions outside the region of MRI-CE, including the adjacent edema and beyond. Metabolic imaging techniques provide visual information about biological processes and have the potential to improve the accuracy of RT tumor delineation and image guided DE. The most studied amino acid tracer is 11C-methionine (11C-MET positron emission tomography [PET]), in which uptake suggests that metabolically active tumor can extend up to 4.5 cm beyond the CE region on CE-MRI and beyond the abnormal T2 signal area for patients with glioma.20,21 11C-MET PET uptake outside the high-dose region defined by CE-MRI is correlated with noncentral recurrences.22 In addition, increasing rates of marginal and distant failures have been reported in patients with MGMT methylation and prolonged survival,23,24 suggesting the importance of re-evaluating RT volume delineation to improve outcomes for glioblastoma in the TMZ era.
The amino acid PET tracer 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) transport is independent of the blood–brain barrier breakdown, allowing uptake to occur in both enhancing and nonenhancing tumor on CE-MRI.14, 15, 16 A comparison of the performance of 18F-DOPA with 11C-MET concluded that 18F-DOPA provided equivalent visual and quantitative specific uptake value (SUV) information when imaging cerebral lesions.18 The short physical half-life of 11C limits the ability to image patients at a facility without a cyclotron. Therefore, labeling an amino acid tracer with F-18 would increase the physical half-life and increase the feasibility of multi-institutional use. The sensitivity for differentiating tumor from normal brain, compelling evidence for amino acid tracers to detect additional tumor beyond conventional CE-MRI, and the feasibility of multi-institutional use led us to further investigate the value of 18F-DOPA PET in the clinical management of glioblastoma.
Our previous work demonstrated that 18F-DOPA has high uptake in tumor tissue, has low uptake in normal brain tissue, and is sensitive and specific for identifying biologically aggressive and residual occult glioma beyond regions of CE.19 The purpose of this prospective phase 2 study was to determine whether 18F-DOPA PET-guided target volume delineation in combination with DERT could improve glioblastoma progression-free survival (PFS) at 6 months depending on MGMT methylation status compared with historical controls (HCs) treated at our institution and on North Central Cancer Treatment Group (NCCTG) prospective clinical trials.
Section snippets
Study population
Between January 2014 and December 2018, patients with newly diagnosed, histologically confirmed glioblastoma were enrolled in this prospective phase 2 clinical trial NCTXXXX (see Fig. E1 for study schema). Patients ≥18 years of age without contraindications to 18F-DOPA PET and who could undergo magnetic resonance imaging (MRI) were eligible to enroll. MGMT assessment was required for study enrollment. Because of the markedly different PFS depending on MGMT methylation status, the limited
Enrollment
A total of 85 patients with newly diagnosed glioblastoma were enrolled on this study (44 unmethylated, 26 methylated, and 15 indeterminate). Seven patients (3 unmethylated, 1 methylated, and 3 indeterminate) did not receive the baseline 18F-DOPA PET owing to either patient decision (requested shorter fractionation schedule, chose to enroll on different study, insurance coverage of radiation) or physician decision (change in patient condition9 and 18F-DOPA PET production disruption9). Three
Conclusion
Our data suggest that biopsy-validated 18F-DOPA PET thresholds could have utility in guiding DERT targeting for glioblastoma. 18F-DOPA PET-guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated patients. OS is significantly improved in MGMT methylated patients compared with HCs. Lack of PFS improvement suggests that pseudoprogression or necrosis affected progression determination; therefore, PFS might not be a reliable indicator of efficacy in DE-Mth patients
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This protocol is registered with ClinicalTrials.gov and can be viewed online at http://clinicaltrials.gov (NCT01991977).
Disclosures: S.K. reports grants paid directly to the institution for clinical execution from Orbus Therapeutics, Apollomics, Celgene, Wayshine Biopharma, and Delmar Therapeutics. V.L. is a consultant for Bayer Schering Pharma, Philips Molecular Imaging, Life Molecular Imaging, AVID Radiopharamceuticals, and GE Healthcare and reports research support from GE Healthcare, Siemens Molecular Imaging, AVID Radio-pharmaceuticals, and the National Institutes of Health (National Institute on Aging, National Cancer Institute).
All data generated and analyzed during this study are included in this published article (and its supplementary information files).