FDOPA-PBT-Glioblastoma
Short-course hypofractionated proton beam therapy, incorporating 18F-DOPA PET and contrast-enhanced MRI targeting, for patients aged 65 years and older with newly diagnosed glioblastoma: a single-arm phase 2 trial
Clinical Question
Can hypofractionated proton beam therapy guided by 18F-DOPA PET and MRI improve survival and quality of life in older patients with newly diagnosed glioblastoma?
Bottom Line
18F-DOPA PET-guided, dose-escalated, hypofractionated proton beam therapy achieved 56% 12-month survival in patients ≥65 years with glioblastoma, exceeding historical controls with acceptable toxicity profile
Major Points
- 56% of patients were alive at 12 months (95% CI 39-72%), exceeding the predefined 33% threshold for success
- Median overall survival of 13.1 months superior to previous hypofractionated radiotherapy studies (5-10 months)
- MGMT methylated patients had significantly longer overall survival (21.8 vs 10.7 months, p=0.011)
- All 39 patients completed planned proton beam therapy course without treatment breaks
- Grade 3 CNS necrosis in 10% of patients, effectively managed with bevacizumab or surgical intervention
Design
Study Type: Single-arm phase 2 trial
Randomization:
Blinding: Open-label
Enrollment Period: May 22, 2019 to May 25, 2021
Follow-up Duration: Median 25.4 months (IQR 22.1-29.7)
Centers: 2
Countries: US
Sample Size: 39
Analysis: Intention-to-treat population (all patients who started radiotherapy)
Inclusion Criteria
- Age ≥65 years
- ECOG performance status 0-2
- Newly diagnosed WHO grade 4 malignant glioblastoma
- Histologically confirmed after surgical resection or biopsy
Exclusion Criteria
- Contraindications to 18F-DOPA PET or MRI
- Unable to obtain imaging
- Estimated glomerular filtration rate <60 mg/min per 1.72 m²
Arms
| Field | 18F-DOPA PET-guided proton beam therapy |
|---|---|
| Intervention | Dose-escalated hypofractionated proton beam therapy (35-40 Gy equivalents in 5 or 10 fractions) with simultaneous integrated boost technique targeting PET T/N ratio >2.0 regions, plus concurrent temozolomide (75 mg/m² daily) followed by adjuvant temozolomide (150-200 mg/m² days 1-5 for six 28-day cycles) |
| Duration | 5-10 days radiotherapy, followed by 6 cycles adjuvant chemotherapy |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Overall survival at 12 months after enrollment | Primary | 22/39 patients (56%) | |||
| 12-month progression-free survival | 95% CI: 19-49% | Secondary | 31% | |||
| Median overall survival | 95% CI: 11.1-19.1 | Secondary | 13.1 months | |||
| Median progression-free survival | 95% CI: 6.0-11.0 | Secondary | 7.1 months | |||
| Any adverse event | Adverse | Grade 1: 30 (77%), Grade 2: 17 (44%), Grade 3: 5 (13%) | |||
| CNS necrosis | Adverse | Grade 1: 14 (36%), Grade 2: 13 (33%), Grade 3: 4 (10%) | |||
| Alopecia | Adverse | Grade 1: 24 (62%), Grade 2: 2 (5%) | |||
| Fatigue | Adverse | Grade 1: 14 (36%) | |||
| Decreased lymphocyte count | Adverse | Grade 1: 4 (10%), Grade 2: 1 (3%) | |||
| Decreased platelet count | Adverse | Grade 1: 3 (8%), Grade 3: 1 (3%) |
Subgroup Analysis
MGMT promoter methylation was significantly associated with improved overall survival in multivariable analysis (HR 6.01, 95% CI 2.02-17.92, p=0.0013). PET gross tumor volume >24.3 cm³ was associated with worse overall survival (HR 3.02, 95% CI 0.76-11.98, p=0.12) and progression-free survival (HR 7.19, 95% CI 1.65-31.30, p=0.0086) in multivariable analysis. Among patients with disease progression, 85% (23/27) maintained their MMSE scores until time of progression.
Criticisms
- Single-arm study design prevents direct comparison with standard photon therapy
- Small sample size (n=39) from homogeneous population (95% White, non-Hispanic)
- 18F-DOPA PET not currently FDA-approved for high-grade glioma imaging
- Proton beam therapy limited availability restricts generalizability
- Uncertainty whether survival benefit due to PET guidance, proton therapy, or hypofractionation
- Post-hoc multivariable analysis should be interpreted cautiously due to small sample size
- Grade 3 CNS necrosis rate of 10% may be concerning, though manageable
Funding
Mayo Clinic Marley Endowment Funds and the Lawrence W and Marilyn W Matteson Fund in Cancer Research
Based on: FDOPA-PBT-Glioblastoma (The Lancet Oncology, 2024)
Authors: Sujay Vora, Deanna Pafundi, Molly Voss, ..., Paul Brown
Citation: Lancet Oncol 2024; 25: 1625-34
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