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

Recruiting at 79 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

Trial Summary

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.

What data supports the effectiveness of this treatment for brain cancer?

Research indicates that hippocampal avoidance whole brain radiotherapy (HA-WBRT) can help preserve neurocognitive function compared to conventional whole brain radiotherapy, making it a promising treatment for patients with brain metastases. ^{1 2 3 4 5}

Is Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) safe for humans?

Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) is designed to reduce cognitive decline compared to standard whole brain radiotherapy, and studies suggest it is generally safe, with a focus on preserving brain function while treating brain metastases. ^{1 3 4 6 7}

How is the treatment of Stereotactic Radiosurgery vs. HA-WBRT + Memantine for brain cancer different from other treatments?

This treatment is unique because it combines Stereotactic Radiosurgery (SRS), which precisely targets brain tumors, with Hippocampal-avoidant Whole Brain Radiation Therapy (HA-WBRT) that spares the hippocampus to reduce memory and cognitive side effects, and memantine, a drug that may help protect brain function. ^{1 2 3 4 5}

What is the purpose of this trial?

Stereotactic radiosurgery (SRS) is a commonly used treatment for brain tumors. It is a one-day (or in some cases two day), out-patient procedure during which a high dose of radiation is delivered to small spots in the brain while excluding the surrounding normal brain. Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) is when radiation therapy is given to the whole brain, while trying to decrease the amount of radiation that is delivered to the area of the hippocampus. The hippocampus is a brain structure that is important for memory. Memantine is a drug that is given to help relieve symptoms that can be caused by WBRT, including problems with memory and other mental symptoms. Health Canada, the regulatory body that oversees the use of drugs in Canada, has not approved the sale or use of memantine in combination with WBRT to treat this kind of cancer, although they have allowed its use in this study.

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

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

Dosimetric evaluation of intensity-modulated radiotherapy, volumetric modulated arc therapy, and helical tomotherapy for hippocampal-avoidance whole brain radiotherapy. [2022]

2. England 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Evaluating the Heterogeneity of Hippocampal Avoidant Whole Brain Radiotherapy Treatment Effect: A Secondary Analysis of NRG CC001. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Radiological distribution of brain metastases and its implication for the hippocampus avoidance in whole brain radiotherapy approach. [2018]

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

Dosimetric feasibility of hippocampal avoidance whole brain radiotherapy with an MRI-guided linear accelerator. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival. [2022]

7. Poland 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. [2023]