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

Trial Summary

What is the purpose of this trial?

This research is being done to assess the quality of life and symptom burden in participants who receive (normal tissue sparing whole brain radiation therapy (NTS-WBRT). This research study involves: * NTS-WBRT (normal tissue sparing whole brain radiation therapy) * Memantine standard of care drug

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.

What data supports the effectiveness of the treatment HA-WBRT for brain cancer?

Research indicates that HA-WBRT (Hippocampal-Avoidant Whole Brain Radiotherapy) can help preserve cognitive function better than traditional whole brain radiotherapy by avoiding damage to the hippocampus, a part of the brain important for memory. Studies also suggest that HA-WBRT may prevent cognitive decline and improve outcomes for patients with brain metastases. ^{1 2 3 4 5}

Is HA-WBRT safe for humans?

HA-WBRT (Hippocampal-Avoidant Whole Brain Radiotherapy) is generally considered safe and may help preserve cognitive function better than traditional whole brain radiotherapy. Studies suggest it can reduce treatment-related cognitive decline, which is a common concern with brain radiation treatments. ^{1 2 3 5 6}

What makes the NTS-WBRT and HA-WBRT treatments unique for brain cancer?

NTS-WBRT and HA-WBRT are unique because they aim to spare healthy brain tissue, particularly the hippocampus, which is important for memory, during whole brain radiation therapy. This approach is designed to reduce cognitive side effects compared to traditional whole brain radiation therapy. ^{7 8 9 10 11}

Research Team

Helen A Shih, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

4. 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]

5. 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]

6. Czech Republic pubmed.ncbi.nlm.nih.gov

Left hippocampus sparing whole brain radiotherapy (WBRT): A planning study. [2022]

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

Auditory verbal learning test can lateralize hippocampal sclerosis. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Developing a comprehensive presurgical functional MRI protocol for patients with intractable temporal lobe epilepsy: a pilot study. [2006]

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

Limitations of Wada memory asymmetry as a predictor of outcomes after temporal lobectomy. [2015]

10. England 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. [2015]

11. Netherlands pubmed.ncbi.nlm.nih.gov

FMRI reveals functional cortex in a case of inconclusive Wada testing. [2013]