Stereotactic Radiosurgery vs. HA-WBRT + Memantine for Brain Cancer

Recruiting at 84 trial locations

Overseen By Chris O'Callaghan

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Canadian Cancer Trials Group

Must not be taking: NMDA antagonists

Disqualifiers: Pregnancy, Prior cranial radiation, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 1

Duration: 1-2 days for SRS or 10 fractions for HA-WBRT

206 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two radiation treatments for brain cancer that has spread. One treatment uses stereotactic radiosurgery, a precise, focused approach targeting small tumor spots. The other involves whole-brain radiation that avoids the hippocampus, the memory-related area, and includes memantine, a drug that helps with memory issues. Researchers aim to determine which treatment is more effective and easier on patients. Individuals with 5 to 15 brain tumors from non-blood cancers who can undergo an MRI might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using NMDA antagonists like amantadine, ketamine, or dextromethorphan.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that hippocampal-avoidant whole brain radiotherapy (HA-WBRT), combined with memantine, helps protect memory and thinking skills in patients. This combination preserves these abilities better than some other treatments. Studies also indicate that it does not worsen patient-reported symptoms. Memantine helps with memory problems often caused by whole brain radiation therapy.

For stereotactic radiosurgery (SRS), research indicates it is generally safe and well-tolerated. This precise, non-surgical treatment uses high doses of radiation to target brain tumors. Studies report a relatively low rate of severe side effects, with only about 7.4% of patients experiencing significant toxic effects.

Both treatments have been studied and show promising safety results. These findings might help ease concerns about safety for those considering participation in a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for brain cancer because they offer targeted approaches that could improve patient outcomes. Unlike traditional whole-brain radiotherapy, which can affect healthy brain tissue, Hippocampal-avoidant Whole Brain Radiotherapy (HA-WBRT) with Memantine specifically spares the hippocampus, potentially reducing cognitive side effects while still effectively treating cancer. Meanwhile, Stereotactic Radiosurgery (SRS) delivers high-dose radiation precisely to tumors in a single session, minimizing exposure to surrounding healthy tissue. These methods aim to enhance the balance between treatment efficacy and quality of life for patients.

What evidence suggests that this trial's treatments could be effective for brain cancer?

This trial will compare two different treatment approaches for brain cancer. One arm involves hippocampal-avoidant whole-brain radiation therapy (HA-WBRT) combined with memantine. Research has shown that HA-WBRT can help protect memory in patients with cancer that has spread to the brain, although adding memantine has produced mixed results; some patients still experience memory and thinking issues. The other arm involves stereotactic radiosurgery (SRS), a precise treatment that targets brain tumors with focused radiation. Studies have found that SRS can effectively control tumors, with a high success rate in preventing recurrence. Both treatments offer potential benefits but work differently in treating brain cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Vina Gondi

Principal Investigator

Northwestern Medicine Cancer Center, Warrenville IL

David Roberge

Principal Investigator

CHUM-Centre Hospitalier de l'Universite de Montreal

Michael Chan

Principal Investigator

Wake Forest School of Medicine, Winston-Salem, NC

Are You a Good Fit for This Trial?

This trial is for adults with 5 to 15 brain metastases from non-blood cancers, where the largest tumor is smaller than 2.5 cm. They must be able to undergo specific types of radiosurgery and HA-WBRT at certified centers, complete neurocognitive tests, and use effective contraception if needed. Excluded are pregnant/nursing individuals, those with allergies to gadolinium or memantine, prior cranial radiation therapy recipients, patients with certain brain conditions or liver disease.

Inclusion Criteria

I can complete quality of life surveys in English or French, with or without help.

The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training

Facility is credentialed by IROC to perform SRS and HA-WBRT

Exclusion Criteria

I have had radiation therapy to my brain before.

I cannot undergo a brain MRI.

I am scheduled for chemotherapy around the time of my radiation treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either stereotactic radiosurgery (SRS) or hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus memantine

1-2 days for SRS or 10 fractions for HA-WBRT

1-2 visits (in-person) for SRS, multiple visits for HA-WBRT

Follow-up

Participants are monitored for safety, effectiveness, and neurocognitive progression-free survival

4.5 years

What Are the Treatments Tested in This Trial?

Interventions

• Hippocampal-avoidant (HA-WBRT) Radiotherapy
• Memantine
• Stereotactic Radiosurgery (SRS)

Trial Overview The study compares Stereotactic Radiosurgery (SRS), a precise one-day radiation treatment targeting tumors while sparing normal brain tissue, against Whole Brain Radiotherapy avoiding the hippocampus (HA-WBRT) plus Memantine which aims to protect memory during whole-brain treatment. The effectiveness in controlling cancer spread within the brain and impact on memory will be assessed.

How Is the Trial Designed?

Group I: Stereotactic Radiosurgery (SRS) Experimental Treatment 1 Intervention

SRS 18-20 or 22Gy in single fraction

Group II: Hippocampal-avoidant (HA-WBRT) plus Memantine Experimental Treatment 2 Interventions

WBRT 30Gy in 10 fractions + memantine

Hippocampal-avoidant (HA-WBRT) Radiotherapy is already approved in United States, Canada, European Union for the following indications:

Approved in United States as HA-WBRT for:

• Brain metastases

Approved in Canada as HA-WBRT for:

• Research use only, not approved for general use

Approved in European Union as HA-WBRT for:

• Brain metastases

Who Is Running the Clinical Trial?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

Alliance for Clinical Trials in Oncology

Collaborator

Trials

521

Recruited

224,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

In a study of 518 patients with brain metastases, those who survived 4 months or longer showed a significant reduction in neurocognitive function failure (NCFF) when treated with hippocampal avoidant whole brain radiotherapy (HA-WBRT) compared to standard WBRT.

Patients with lower baseline cognitive impairment (as measured by the MD Anderson Symptom Inventory-Brain Tumor scores) and those with primary lung tumors experienced greater neuroprotective benefits from HA-WBRT, highlighting the importance of individual patient characteristics in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the Heterogeneity of Hippocampal Avoidant Whole Brain Radiotherapy Treatment Effect: A Secondary Analysis of NRG CC001. Cherng, HR., Sun, K., Bentzen, S., et al.[2023]

In a study of 226 patients with brain metastases, only a small percentage (8.4%) showed involvement of the hippocampus within a 20 mm margin, suggesting that hippocampus avoidance in whole brain radiotherapy (HA-WBRT) is feasible and may help preserve cognitive function.

The analysis indicated that having six or more brain metastases significantly increases the risk of hippocampal involvement, which is crucial for optimizing treatment planning and margin definitions in HA-WBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiological distribution of brain metastases and its implication for the hippocampus avoidance in whole brain radiotherapy approach. Han, YM., Cai, G., Chai, WM., et al.[2018]

The study shows that whole brain radiotherapy with hippocampal avoidance (HA-WBRT) can be effectively delivered using an MRI-guided linear accelerator, maintaining treatment quality and accuracy comparable to traditional non-MRI-guided methods.

MRI-guided plans resulted in slightly higher doses to the hippocampus but still met clinical goals, indicating that this advanced technology can help preserve cognitive function while treating metastatic brain disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric feasibility of hippocampal avoidance whole brain radiotherapy with an MRI-guided linear accelerator. Graham, JA., Redler, G., Delozier, KB., et al.[2022]

Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) combined with a simultaneous integrated boost (SIB) showed a local tumor control rate of 73% and a median intracranial progression-free survival of 40 weeks in a study of 20 patients.

The treatment was found to be safe, with no significant acute or late toxicities observed, suggesting it may help prevent cognitive decline associated with standard whole brain radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival. Oehlke, O., Wucherpfennig, D., Fels, F., et al.[2022]

TomoTherapy is the most effective method for Hippocampal Avoidance Whole Brain Radiotherapy (HA-WBRT), providing a significantly better dose distribution compared to IMRT and RapidArc, as indicated by a superior homogeneity index.

RapidArc, while not as effective in dose distribution as TomoTherapy, offers the fastest treatment delivery time, making it a suitable alternative when time efficiency is a priority.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric evaluation of intensity-modulated radiotherapy, volumetric modulated arc therapy, and helical tomotherapy for hippocampal-avoidance whole brain radiotherapy. Rong, Y., Evans, J., Xu-Welliver, M., et al.[2022]

In a study involving 65 patients with brain metastases, hippocampal avoidance whole-brain radiotherapy (HA-WBRT) demonstrated better preservation of memory function at 6 months compared to conformal WBRT (C-WBRT), particularly in recognition and memory scores.

Despite the cognitive benefits observed with HA-WBRT, there were no significant differences in overall survival or brain progression-free survival between the two treatment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial. Yang, WC., Chen, YF., Yang, CC., et al.[2021]

Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) effectively preserves neurocognitive function in patients with brain metastasis, showing a significant decrease in cognitive decline over 12 months after treatment.

Patients treated with HA-WBRT also experienced improvements in quality of life, particularly in social well-being, indicating that this treatment not only controls disease but also enhances overall patient well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hippocampal avoidance whole brain radiotherapy in brain metastasis using volumetric modulated arc therapy: experience from a Regional Cancer Centre of Eastern India. Deepsikha, G., Maji, T., Lahiri, D., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7992885/

Hippocampal avoidance whole-brain radiotherapy without ... Patients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.

2. journals.lww.com journals.lww.com/neur/fulltext/2025/07000/hippocampal_avoidance__whole_brain_radiotherapy.10.aspx

Hippocampal Avoidance -Whole Brain Radiotherapy (HA- ... In this phase II trial, patients with brain metastases who received HA-WBRT showed significantly better preservation of cognitive functions, particularly memory ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2039

Initial report of memory avoidance whole brain ... However, a subset of patients who receive HA-WBRT with memantine still experience cognitive decline. Other brain structures with important roles ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02360215

Study Details | NCT02360215 | Memantine Hydrochloride ... This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing ...

5. mayo.edu mayo.edu/research/clinical-trials/cls-20306527

Memantine Hydrochloride and Whole-Brain Radiotherapy ... This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32058845/

Phase III Trial NRG Oncology CC001 - PubMed - NIH HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS.

7. redjournal.org redjournal.org/article/S0360-3016(23)00438-8/abstract

Final Results of NRG Oncology CC001 Sustained preservation of cognition and prevention of patient-reported symptoms with hippocampal avoidance during whole-brain radiation therapy for brain ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.20.00747

Hippocampal Avoidance and Memantine for Whole-Brain ... Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) in combination with memantine as a new standard of care for patients with newly diagnosed brain ...