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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

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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

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	Intervention
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

Content summarized and formatted by NeuroTrials.ai.

FDOPA-PBT-Glioblastoma

(2024)

Objective

To test whether hypofractionated proton beam therapy guided by 18F-DOPA PET and MRI can improve survival and quality of life in patients aged 65 years and older with newly diagnosed glioblastoma

Study Summary

• 56% of patients (22/39) were alive at 12 months (95% CI 39-72%), exceeding the 33% historical control threshold
• Median overall survival was 13.1 months (95% CI 11.1-19.1), superior to previous hypofractionated studies (5-10 months)
• Grade 3 CNS necrosis occurred in 10% (4/39) of patients, manageable with bevacizumab or surgery

Intervention

Dose-escalated hypofractionated proton beam therapy (35-40 Gy equivalents) delivered in 5 or 10 fractions using 18F-DOPA PET T/N ratio >2.0 to define highest-dose regions and MRI contrast enhancement, with concurrent temozolomide (75 mg/m² daily) followed by adjuvant temozolomide

Inclusion Criteria

Patients aged ≥65 years with ECOG performance status 0-2 and newly diagnosed WHO grade 4 glioblastoma after surgical resection or biopsy

Study Design

Arms: Single-arm: 18F-DOPA PET-guided dose-escalated hypofractionated proton beam therapy with temozolomide

Patients per Arm: 39 patients (intention-to-treat population)

Outcome

• Primary: 12-month overall survival rate 56% (95% CI 39-72%)
• Secondary: 12-month progression-free survival 31% (95% CI 19-49%); median progression-free survival 7.1 months (95% CI 6.0-11.0)
• Safety: Grade 3 CNS necrosis 10%, Grade 3 thrombocytopenia 3%, no Grade 4 events or treatment-related deaths

Bottom Line

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

Study Design

Study Type: Single-arm phase 2 trial
Randomization: No
Blinding: Open-label
Sample Size: 39
Follow-up: Median 25.4 months (IQR 22.1-29.7)
Centers: 2
Countries: US

Primary Outcome

Definition: Overall survival at 12 months after enrollment

Control	Intervention	HR/OR	P-value
	22/39 patients (56%)	- (39-72%)

Limitations & 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

Citation

Lancet Oncol 2024; 25: 1625-34

View Original Publication →

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

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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