← Back
NeuroTrials.ai
Neurology Clinical Trial Database

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

Share Share Copied! Compare

Year of Publication: 2024

Authors: Sujay Vora, Deanna Pafundi, Molly Voss, ..., Paul Brown

Journal: The Lancet Oncology

Citation: Lancet Oncol 2024; 25: 1625-34

Link: https://doi.org/10.1016/S1470-2045(24)00585-0

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

Baseline Characteristics

Overall:

  • Age - Median (IQR): 70.2 (67.4-74.3) years
  • Sex - Male: 28 (72%)
  • Sex - Female: 11 (28%)
  • Race - White: 37 (95%)
  • Race - Black or African American: 1 (3%)
  • Race - Choose not to disclose: 1 (3%)
  • Ethnicity - Not Hispanic or Latino: 38 (97%)
  • Geographical area - Rural: 7 (18%)
  • Geographical area - Non-rural: 32 (82%)
  • Lesion diameter - Median (IQR): 5.1 (3.8-7.4) cm
  • Tumour distribution - Unifocal: 29 (74%)
  • Tumour distribution - Multifocal: 10 (26%)
  • Tumours crossing midline: 8 (21%)
  • Extent of surgery - Gross total resection: 16 (41%)
  • Extent of surgery - Subtotal resection: 8 (21%)
  • Extent of surgery - Biopsy only: 15 (38%)
  • Neurological deficit: 13 (33%)
  • History of seizures: 10 (26%)
  • ECOG performance status 0: 12 (31%)
  • ECOG performance status 1: 20 (51%)
  • ECOG performance status 2: 7 (18%)
  • Wildtype IDH: 39 (100%)
  • MGMT promoter status - Methylated: 13 (33%)
  • MGMT promoter status - Unmethylated: 24 (62%)
  • MGMT promoter status - Data not available: 2 (5%)
  • Pretreatment MMSE score - Median (IQR): 27 (24-29)
  • Corticosteroid use at study entry: 21 (54%)
  • PET volume - Median (IQR): 8.0 (4.0-24.3) cm³
  • MRI volume - Median (IQR): 35.1 (20.7-60.8) cm³
  • EORTC QLQ-C30 score at baseline - Median (IQR): 5 (4-6)

Arms

Field18F-DOPA PET-guided proton beam therapy
InterventionDose-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)
Duration5-10 days radiotherapy, followed by 6 cycles adjuvant chemotherapy

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Overall survival at 12 months after enrollmentPrimary22/39 patients (56%)
12-month progression-free survival | 95% CI: 19-49%Secondary31%
Median overall survival | 95% CI: 11.1-19.1Secondary13.1 months
Median progression-free survival | 95% CI: 6.0-11.0Secondary7.1 months
Any adverse eventAdverseGrade 1: 30 (77%), Grade 2: 17 (44%), Grade 3: 5 (13%)
CNS necrosisAdverseGrade 1: 14 (36%), Grade 2: 13 (33%), Grade 3: 4 (10%)
AlopeciaAdverseGrade 1: 24 (62%), Grade 2: 2 (5%)
FatigueAdverseGrade 1: 14 (36%)
Decreased lymphocyte countAdverseGrade 1: 4 (10%), Grade 2: 1 (3%)
Decreased platelet countAdverseGrade 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

Content summarized and formatted by NeuroTrials.ai.