TY - JOUR
T1 - Initial Results of a Phase 2 Trial of 18F-DOPA PET-Guided Dose-Escalated Radiation Therapy for Glioblastoma
AU - Laack, Nadia Nicole
AU - Pafundi, Deanna
AU - Anderson, S. Keith
AU - Kaufmann, Timothy
AU - Lowe, Val
AU - Hunt, Christopher
AU - Vogen, Diane
AU - Yan, Elizabeth
AU - Sarkaria, Jann
AU - Brown, Paul
AU - Kizilbash, Sani
AU - Uhm, Joon
AU - Ruff, Michael
AU - Zakhary, Mark
AU - Zhang, Yan
AU - Seaberg, Maasa
AU - Wan Chan Tseung, Hok Seum
AU - Kabat, Brian
AU - Kemp, Bradley
AU - Brinkmann, Debra
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Purpose: Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18F-DOPA PET in patients with glioblastoma. Methods and Materials: Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6‐methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0. Results: Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; P = .017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; P = .13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; P = .049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; P = .26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases. Conclusions: 18F-DOPA PET–guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18F-DOPA PET biologic guided DERT for glioblastoma is warranted.
AB - Purpose: Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18F-DOPA PET in patients with glioblastoma. Methods and Materials: Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6‐methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0. Results: Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; P = .017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; P = .13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; P = .049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; P = .26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases. Conclusions: 18F-DOPA PET–guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18F-DOPA PET biologic guided DERT for glioblastoma is warranted.
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U2 - 10.1016/j.ijrobp.2021.03.032
DO - 10.1016/j.ijrobp.2021.03.032
M3 - Article
C2 - 33771703
AN - SCOPUS:85105745983
SN - 0360-3016
VL - 110
SP - 1383
EP - 1395
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 5
ER -