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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating glioblastoma or Grade 4 astrocytoma in individuals aged 65 and older. It seeks to determine if a higher dose of radiation over three weeks, combined with new technology for daily treatment adjustments, can improve survival rates. The treatment involves dose escalation and reduced margin adaptive radiotherapy, along with chemotherapy using temozolomide, employing a machine that precisely targets the tumor. Suitable participants have been diagnosed with these brain tumors and are deemed appropriate for a three-week radiation course by their doctors. The trial aims to offer better outcomes through a more tailored treatment plan. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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 prior data suggests that this adaptive radiotherapy is safe for glioblastoma patients?

Research shows that a new approach to treating glioblastoma, which involves higher radiation doses over a shorter period, is well-tolerated by patients. Studies have found that administering a higher dose of radiation over three weeks, similar to the regimen for younger patients, improves survival rates without causing serious side effects.

Additionally, evidence supports the use of MR-Linac technology. This technology enables doctors to take daily MRI scans during treatment, allowing them to adjust the radiation to match tumor changes. One study found that this method, which uses smaller radiation margins, is safe and does not cause severe side effects. Patients experienced fewer serious side effects while still receiving effective treatment.

Overall, these findings suggest that this new treatment approach is safe for people with glioblastoma, offering a good balance between higher radiation doses and fewer side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about the adaptive radiotherapy approach for glioblastoma because it uses cutting-edge MR-Linac technology to deliver precise radiation doses while adapting to changes in tumor size and position. Unlike standard treatments that use fixed radiation doses, this method allows for dose escalation and reduced margins, potentially improving effectiveness while minimizing damage to surrounding healthy tissue. Additionally, combining this adaptive technique with the chemotherapy drug temozolomide (TMZ) in a more targeted manner may enhance tumor control and patient outcomes. This innovative approach could represent a significant advance in glioblastoma treatment.

What evidence suggests that dose escalation and reduced margin adaptive radiotherapy might be effective for glioblastoma?

Research has shown that administering the same higher radiation dose to older glioblastoma patients as given to younger patients can improve survival rates and is well-tolerated. In this trial, participants will receive dose-escalated chemoradiation with temozolomide (TMZ) using adaptive radiotherapy, which adjusts treatment based on daily MRI scans. This method helps focus the radiation more accurately on the tumor. Studies indicate this approach reduces the chance of missing the tumor, with only a small risk of missing the target. It also protects healthy tissue and allows for safely increasing the radiation dose. Overall, these findings suggest that increasing the radiation dose along with adaptive radiotherapy might lead to better outcomes for glioblastoma patients. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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]

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]

Citations

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Evolving concepts in margin strategies and adaptive ... The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities.

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Magnetic resonance imaging in glioblastoma radiotherapy The purpose of the study was to examine the safety of adaptive radiotherapy in glioblastoma, using a margin-reduction approach based on an interim magnetic ...

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MRI-Guided Adaptive Radiation Therapy Using adaptive CBCT-guided radiation therapy approximately 10% to 30% of patients have required re-planning, especially when treated with chemoradiation.

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Advancements in adaptive MR-guided radiotherapy for ... The study, similar to the existing literature, demonstrated a low risk of marginal failure (4.1%, 95% CI: 1.6–10%), establishing non-inferiority ...

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Adaptive Radiotherapy Plans reflect each patient's daily anatomy, reducing toxicity, protecting organs at risk, and enabling safe dose escalation with evidence of improved outcomes.

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MR-Linac On-Line Weekly Adaptive Radiotherapy for High ... We present the first trial evaluating on-line MRL weekly adaptive chemoRT for HGG with a limited CTV. Safety and feasibility was demonstrated ...

7. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2818117

Safety and Tolerability of Online Adaptive High-Field ... The findings of this study suggest that online adaptive MR-guided radiotherapy is associated with a low risk of high-grade acute toxic effects.

8. cancernetwork.com cancernetwork.com/view/adaptive-radiotherapy-modality-appears-safe-feasible-in-high-grade-glioma

Adaptive Radiotherapy Modality Appears Safe, Feasible in ... The mean reduction in treated CTV margins was 40% with the adaptive radiotherapy modality compared with the European Organisation for Research ...