NTS-WBRT vs. HA-WBRT for Brain Cancer

Overseen By Helen A Shih, MD,MS, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: NMDA antagonists

Disqualifiers: Leptomeningeal disease, Prior WBRT, others

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

Compensation: Varies

Number of Visits: 7

Duration: 2-3 weeks

41 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two types of whole brain radiation therapy (WBRT) affect the quality of life and symptoms in people with brain cancer. The main focus is to compare normal tissue sparing WBRT (NTS-WBRT), which limits damage to healthy brain tissue, with hippocampal avoiding WBRT (HA-WBRT). Participants will also receive Memantine, a standard drug that aids brain function. People with solid tumors and brain metastases who require WBRT and can undergo MRI scans may be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to advancements in brain cancer care.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it allows any prior, concurrent, or post-radiotherapy systemic therapy at the discretion of your treating physician. You cannot participate if you are currently using memantine or other NMDA antagonists.

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

Research is investigating a treatment called NTS-WBRT, which stands for normal tissue sparing whole brain radiation therapy, to assess its safety and effectiveness for brain cancer. The studies are still gathering detailed safety information. Since the research is ongoing, some early safety results are available, but they are not yet final.

Memantine, a common medication used with NTS-WBRT, has more information available. Research has shown that memantine is generally safe. In one study, it was used with other treatments and was well-tolerated by patients with brain tumors. Another study found that memantine helped improve thinking skills over time compared to a placebo, indicating it does not have major harmful effects.

In summary, while NTS-WBRT is still under study, memantine has a good safety record. Both treatments aim to reduce harm, and ongoing research will provide clearer safety details. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about NTS-WBRT (normal tissue sparing whole brain radiation therapy) for brain cancer because it focuses on protecting healthy brain tissue while effectively targeting cancer cells. Unlike traditional whole brain radiation therapy, which can affect both cancerous and healthy brain tissues, NTS-WBRT aims to minimize damage to normal tissue. This approach has the potential to reduce side effects and improve quality of life for patients undergoing treatment. Additionally, the use of Memantine alongside NTS-WBRT may help in reducing cognitive decline, providing a more comprehensive treatment option for patients.

What evidence suggests that NTS-WBRT and HA-WBRT could be effective for brain cancer?

Research has shown that normal tissue sparing whole brain radiation therapy (NTS-WBRT), which participants in this trial may receive, can help prevent problems with thinking and memory in patients with cancer that has spread to the brain. In a study of 518 patients, those who lived for 4 months or more demonstrated better thinking and memory skills compared to those who received other types of radiation treatments. This trial combines NTS-WBRT with a medication called memantine, which can further protect against the thinking and memory issues often caused by radiation. Studies have found that memantine improved thinking and memory after 24 weeks compared to a placebo (a pill with no active medicine). Together, these treatments aim to preserve brain function while treating brain cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Helen A Shih, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults with brain metastases from solid tumors, who can have an MRI and are expected to live more than 6 months. They should be able to perform daily activities well (Karnofsky score ≥70), understand English, consent in writing, and return for follow-ups for up to 2 years. Pregnant women or those using certain drugs like memantine are excluded.

Inclusion Criteria

My doctor may allow previous targeted brain radiation.

I've had brain radiation, but less than half of my brain was treated, as decided by my doctor.

Ability to return for follow-up examinations throughout the course of this study for a maximum of 2 years after radiation treatment completion

Exclusion Criteria

I have been diagnosed with leptomeningeal disease.

I do not have any severe illnesses that could affect my thinking or compliance with the study.

Known allergy to contrast used in imaging studies and/or inability to have MRI imaging

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NTS-WBRT for 5 days per week for either 2 or 3 weeks, along with Memantine as standard of care

2-3 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of quality of life and symptom burden

4 months

Regular follow-up visits at baseline, 2, 4, 6, 9, 12, 18, and 24 months

Long-term follow-up

Participants are monitored for overall survival and other secondary outcomes

Up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• HA-WBRT
• Memantine
• NTS-WBRT

Trial Overview The trial compares two radiation therapies: NTS-WBRT which spares normal tissue, and HA-WBRT that avoids the hippocampus area of the brain. Both groups will also receive Memantine. The goal is to see which treatment better maintains quality of life.

How Is the Trial Designed?

Group I: NTS-WBRT (normal tissue sparing whole brain radiation therapy) + Memantine Experimental Treatment 2 Interventions

Participants will be randomly assigned to NTS-WBRT (normal tissue sparing whole brain radiation therapy) administration group and receive: * NTS-WBRT for 5 days (Monday-Friday) for either 2 or 3 weeks. * Memantine per standard of care, 1-2x daily for up to 24 weeks Specific participant administration schedules will be determined by study doctor

HA-WBRT is already approved in United States, European Union for the following indications:

Approved in United States as Hippocampal-Avoidant Whole Brain Radiotherapy for:

• Brain metastases from small cell lung cancer
• Other brain metastases

Approved in European Union as Hippocampal-Avoidant Whole Brain Radiotherapy for:

• Brain metastases from various cancers

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

A new fMRI protocol was developed and tested on nine healthy right-handed subjects, showing effective localization of language and memory functions in the brain, which could serve as an alternative to the traditional Wada test for patients with temporal lobe epilepsy.

The protocol demonstrated reliable activation maps for memory and language tasks, particularly highlighting the ability to identify critical areas in the left anterior temporal pole and middle temporal gyrus, which are important for surgical planning in epilepsy treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing a comprehensive presurgical functional MRI protocol for patients with intractable temporal lobe epilepsy: a pilot study. Deblaere, K., Backes, WH., Hofman, P., et al.[2006]

In a unique case study of an epileptic patient, the Wada test indicated a neuroplastic shift of motor and language functions to the right hemisphere, despite the patient showing no dysfunction after left carotid injection.

However, motor fMRI revealed strong activation in the left hemisphere during right hand movements, suggesting that fMRI can uncover residual functional areas that the Wada test may miss, highlighting its potential as a complementary tool in assessing hemispheric dominance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FMRI reveals functional cortex in a case of inconclusive Wada testing. Lanzenberger, R., Wiest, G., Geissler, A., et al.[2013]

The Wada test, while invasive, is crucial for assessing memory and language dominance in patients undergoing neurosurgery, particularly for those with right hemispheric seizure onset.

Two atypical cases demonstrated that the Wada test can reveal unexpected lateralization of memory and language functions, highlighting the need for careful evaluation using both functional MRI and Wada testing even when lesions appear typical.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of the Wada test and functional magnetic resonance imaging in preoperative mapping of language and memory: two atypical cases. Połczyńska, MM., Benjamin, CF., Moseley, BD., et al.[2015]

In a study of 227 patients undergoing anterior temporal lobectomy (ATL), 36% of those with left ATL showed unexpected memory asymmetry (UA), which was linked to worse surgical outcomes at 1 year for right ATL patients, but not for left ATL patients.

The study found no correlation between Wada memory asymmetry and persistent changes in verbal memory after surgery, suggesting that Wada test results may not reliably predict postoperative memory outcomes, particularly in patients undergoing left ATL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limitations of Wada memory asymmetry as a predictor of outcomes after temporal lobectomy. Kirsch, HE., Walker, JA., Winstanley, FS., et al.[2015]

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]

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]

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]

Unilateral sparing of the left hippocampus during whole brain radiotherapy (LHA-WBRT) shows promise in improving target coverage and reducing radiation exposure to the hippocampus, which may help mitigate cognitive decline, particularly in verbal memory.

In a study involving 10 patients, LHA-WBRT plans demonstrated a significant reduction in the dose received by the left hippocampus compared to standard bilateral hippocampus avoidance (HA-WBRT), suggesting potential benefits that warrant further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left hippocampus sparing whole brain radiotherapy (WBRT): A planning study. Kazda, T., Vrzal, M., Prochazka, T., 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]

The Auditory Verbal Learning Test (AVLT) effectively differentiates between left and right hippocampal sclerosis in patients with mesial temporal lobe epilepsy, with four specific AVLT scores showing strong classification accuracy.

In right-handed patients, combining the delayed recall trial with the learning over trials index significantly improved diagnostic accuracy to 85%, highlighting the AVLT's potential as a reliable tool for assessing verbal memory related to hippocampal laterality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auditory verbal learning test can lateralize hippocampal sclerosis. Cavaco, S., Moreira, B., Dias, D., et al.[2022]

Citations

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Memantine in radiation-induced cognitive dysfunction ... At 24 weeks, memantine arm improved ACE scores by +4 (0 to 12) compared to placebo -8 (-15.5 to -2.5) (p < 0.001). At 24 weeks in WBRT, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0093775423000659

Efficacy of memantine in preventing neurocognitive ... About 50%–90% of patients with brain metastases who receive radiation therapy experience cognitive impairment. This systematic review aims to gather credible ...

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Memantine for the prevention of cognitive dysfunction in ... Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and ...

4. cancer.gov cancer.gov/news-events/cancer-currents-blog/2018/brain-metastases-radiation-therapy-hippocampal-avoidance

Tailored Radiation for Brain Metastases Reduces ... In the NCI-funded trial, patients with brain metastases were treated with the drug memantine (Namenda), which has been shown to help protect ...

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An Updated Review on Memantine Efficacy in Reducing ... It seems reasonable to consider Memantine during radiation to prevent long-term cognitive failure in patients with brain metastasis due to the current results.

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7. clinicaltrials.gov clinicaltrials.gov/study/NCT04939597

NCT04939597 | A Study to See if Memantine Protects the ... To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo. VII. To correlate changes in ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10134315/

A phase II single‐arm trial of memantine for prevention of ... Stable or improved cognition was observed in 87%–91% across objective cognitive domain composite measures. Sixty‐six percent self‐reported ...