Adaptive Radiotherapy for Glioblastoma

(UNITED2 Trial)

Overseen By Chia-Lin (Eric) Tseng, MD

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sunnybrook Health Sciences Centre

Must be taking: Temozolomide

Disqualifiers: MRI contraindications, Brainstem disease, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

55 Participants Needed

Trial Summary

What is the purpose of this trial?

The usual standard of care for patients over 65 diagnosed with glioblastoma ("GBM") or Grade 4 astrocytoma, IDH-mutant is a 3-week course of radiotherapy, with concurrent and adjuvant temozolomide (TMZ). This radiation dose and length of treatment are less than what would be given for younger patients, primarily due to unclear survival benefits from randomized trials. However, survival remains dismal, and may be partially due to the reduced radiation dose. Recent studies investigating this have found that increased radiation dose (to the equivalent of what is normally given over 6 weeks in younger patients) over 3 weeks is well-tolerated and has improved survival rates. Additionally, with the advent of novel technology such as the MR-Linac, adaptive radiotherapy with this regimen using reduced radiation margins is possible. Use of the MR-Linac allows for daily MRI scans to be done prior to treatment, so plans can be adapted to tumour dynamics and anatomical deformations. In this trial, we will examine the outcomes of increased radiation dose, combined with reduced-margin adaptive radiotherapy in this patient population.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you will be receiving temozolomide chemotherapy alongside radiation treatment, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Adaptive Radiotherapy for Glioblastoma?

Research shows that using MRI-linear accelerators (MR-Linacs) for adaptive radiotherapy can help target treatment-resistant areas in glioblastoma, potentially improving survival. Additionally, adaptive planning can reduce radiation exposure to healthy brain areas, which may lessen side effects and improve cognitive function after treatment. ^{1 2 3 4 5}

Is adaptive radiotherapy for glioblastoma safe for humans?

Research on adaptive radiotherapy, including dose escalation and MR-Linac systems, shows that it can be safely administered with careful planning. Studies have reported mild acute side effects like nausea, and while some patients needed steroids, serious late side effects were rare. ^{2 5 6 7 8}

How is the treatment 'Adaptive Radiotherapy for Glioblastoma' different from other treatments for this condition?

This treatment is unique because it uses MRI-guided technology to adapt the radiation plan daily, allowing for precise targeting of the tumor while sparing healthy brain tissue. This approach can potentially reduce side effects and improve outcomes by adjusting to changes in the tumor and surrounding anatomy during the treatment course. ^{1 4 5 6 9}

Eligibility Criteria

This trial is for people over 65 with a recent diagnosis of glioblastoma or Grade 4 astrocytoma, IDH-mutant. They must have had surgery or biopsy within the last 6 weeks and be fit enough for daily radiation treatments over three weeks alongside chemotherapy. Participants need to expect to live at least another 12 weeks, be able to do some quality of life questionnaires in English, and have kidneys working well enough for MRI contrast.

Inclusion Criteria

Completed written informed consent

Patient must be accessible for treatment and follow-up

I am 65 years old or older.

Exclusion Criteria

I have previously received high-dose radiation to my brain.

Contraindication to Gadolinium-based contrast media

I cannot lie flat on my back for 90 minutes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 3-week course of dose-escalated chemoradiation with temozolomide (TMZ) using MR-Linac with weekly adaptation

3 weeks

Daily visits for radiation treatment

Follow-up

Participants are monitored for safety, effectiveness, and quality of life changes after treatment

9 months

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

12-24 months

Treatment Details

Interventions

• Dose escalation + Reduced Margin Adaptive Radiotherapy

Trial Overview The study tests if giving a higher dose of radiation (like what younger patients get) over three weeks using MR-Linac technology can help older patients with high-grade brain tumors better than standard treatment. The MR-Linac allows doctors to adjust the plan daily based on MRI scans before each treatment session.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

Concurrent dose-escalated chemoradiation with temozolomide (TMZ) on the MR-Linac with weekly adaptation

Dose escalation + Reduced Margin Adaptive Radiotherapy is already approved in United States, European Union for the following indications:

Approved in United States as MR-Linac Radiation Therapy for:

• High-grade glioma in the elderly
• Glioblastoma
• Grade 4 astrocytoma, IDH-mutant

Approved in European Union as MR-Linac Radiation Therapy for:

• High-grade glioma in the elderly
• Glioblastoma
• Grade 4 astrocytoma, IDH-mutant

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Findings from Research

In a study of 10 glioblastoma patients undergoing radiation therapy, weekly adaptive planning using MRI-Linac systems significantly reduced radiation doses to healthy brain structures, particularly the hippocampi, compared to static planning.

The adaptive planning resulted in a maximum dose reduction to the hippocampi from 21 Gy to 15.2 Gy and a mean dose reduction from 12.5 Gy to 8.4 Gy, suggesting that this approach could help minimize neurocognitive side effects associated with radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simulated Adaptive Radiotherapy for Shrinking Glioblastoma Resection Cavities on a Hybrid MRI-Linear Accelerator. Guevara, B., Cullison, K., Maziero, D., et al.[2023]

In a phase II study involving 66 patients with glioblastoma multiforme, accelerated radiotherapy with escalating doses (up to 60 Gy) showed mild acute toxicity, with 91% of patients experiencing no nausea or vomiting.

The treatment resulted in neurological improvement or stability in 80% of patients, indicating efficacy, although higher doses (60 Gy) were associated with a greater need for steroids, suggesting a potential increase in late toxicity risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study. González, DG., Menten, J., Bosch, DA., et al.[2019]

The study involved 20 patients (14 with single lymph node oligometastases and 6 with multiple metastases) treated with a 1.5T MR-linac, which showed comparable target coverage for tumor volumes when compared to conventional CBCT-linac treatments.

Using the MR-linac improved the percentage of treatment plans meeting all dose constraints significantly, from 19% to 84% for single lymph node cases and from 20% to 67% for multiple lymph node cases, indicating enhanced precision in delivering radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target coverage and dose criteria based evaluation of the first clinical 1.5T MR-linac SBRT treatments of lymph node oligometastases compared with conventional CBCT-linac treatment. Winkel, D., Bol, GH., Werensteijn-Honingh, AM., et al.[2021]

Daily full online replanning using the MR-linac system is the most effective method for adapting radiotherapy plans, ensuring that all clinical dose constraints are met for various tumor sites, including prostate and lymph node oligometastases.

The time required for plan adaptation varies significantly, ranging from 17 to 485 seconds, indicating that while faster methods exist, they may not always provide the same level of dosimetric accuracy and should be evaluated for specific clinical scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adaptive radiotherapy: The Elekta Unity MR-linac concept. Winkel, D., Bol, GH., Kroon, PS., et al.[2023]

In a study of 75 glioblastoma patients undergoing chemoradiotherapy, changes in low-ADC regions measured by MR-Linac diffusion-weighted imaging (DWI) were found to be prognostic for overall survival (OS), indicating that this imaging technique can effectively assess treatment response.

The study revealed that changes in low-ADC regions correlated more strongly with OS and progression-free survival (PFS) than traditional measurements of the contrast-enhancing gross tumor volume (GTV), suggesting that low-ADC areas could be targeted for dose escalation in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffusion-weighted imaging on an MRI-linear accelerator to identify adversely prognostic tumour regions in glioblastoma during chemoradiation. Lawrence, LSP., Chan, RW., Chen, H., et al.[2023]

A new method for online automatic 3D secondary dose calculation (SDC) for 1.5T MR-Linac systems was developed and validated, showing high accuracy with a median gamma passing rate of 98.9% compared to full dose calculations in clinical plans.

This method demonstrated effective performance in clinical settings, particularly for central target locations, but additional verification may be needed for cases with peripheral targets and fewer beams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automatic 3D Monte-Carlo-based secondary dose calculation for online verification of 1.5 T magnetic resonance imaging guided radiotherapy. Nachbar, M., Mönnich, D., Dohm, O., et al.[2022]

The MR-Linac treatment planning system (TPS) successfully generated high-quality plans for stereotactic body radiation therapy (SBRT) in 15 pancreatic cancer patients, achieving lower doses to organs at risk (OAR) while maintaining effective target coverage.

The MR-Linac TPS allowed for isotoxic dose escalation, increasing the prescription dose from 25 Gy to an average of 36 Gy, demonstrating its potential for enhanced treatment efficacy through real-time target tracking and improved dose delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of Isotoxic Dose Escalation and Plan Quality with TDABC Analysis on a 0.35 T MR-Linac (MRL) System in Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy (MRgRT) for Primary Pancreatic Cancer. Hawranko, R., Sohn, JJ., Neiderer, K., et al.[2022]

A proactive risk analysis identified 89 potential hazards in the workflow of on-table adaptive radiotherapy using MR-guided linear accelerators, highlighting the importance of safety in this complex treatment process.

After implementing mitigation strategies, all identified risks were reduced to acceptable levels, emphasizing the need for standardized protocols and checklists to enhance safety and efficiency in radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A practical implementation of risk management for the clinical introduction of online adaptive Magnetic Resonance-guided radiotherapy. Klüter, S., Schrenk, O., Renkamp, CK., et al.[2022]

The MR-linac system demonstrated reliable performance in adaptive radiation therapy for gynecologic cancers, with over 90% of treatment plans passing quality assurance tests, indicating high accuracy and safety in treatment delivery.

Treatment durations were significantly shorter when using the position adaptation method (ATP) compared to the shape adaptation method (ATS), with median times of 30 minutes versus 42 minutes, respectively, enhancing the efficiency of the therapy process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Implementation and Initial Experience With a 1.5 Tesla MR-Linac for MR-Guided Radiation Therapy for Gynecologic Cancer: An R-IDEAL Stage 1 and 2a First in Humans Feasibility Study of New Technology Implementation. Lakomy, DS., Yang, J., Vedam, S., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Simulated Adaptive Radiotherapy for Shrinking Glioblastoma Resection Cavities on a Hybrid MRI-Linear Accelerator. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Accelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study. [2019]

3. Ireland pubmed.ncbi.nlm.nih.gov

Target coverage and dose criteria based evaluation of the first clinical 1.5T MR-linac SBRT treatments of lymph node oligometastases compared with conventional CBCT-linac treatment. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Adaptive radiotherapy: The Elekta Unity MR-linac concept. [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Diffusion-weighted imaging on an MRI-linear accelerator to identify adversely prognostic tumour regions in glioblastoma during chemoradiation. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Automatic 3D Monte-Carlo-based secondary dose calculation for online verification of 1.5 T magnetic resonance imaging guided radiotherapy. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Investigation of Isotoxic Dose Escalation and Plan Quality with TDABC Analysis on a 0.35 T MR-Linac (MRL) System in Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy (MRgRT) for Primary Pancreatic Cancer. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A practical implementation of risk management for the clinical introduction of online adaptive Magnetic Resonance-guided radiotherapy. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Clinical Implementation and Initial Experience With a 1.5 Tesla MR-Linac for MR-Guided Radiation Therapy for Gynecologic Cancer: An R-IDEAL Stage 1 and 2a First in Humans Feasibility Study of New Technology Implementation. [2023]