SMART Trial: Cognitive Sparing Brain Radiotherapy for Multiple Brain Metastases

Stereotactic RadioSurgery Versus Memantine Plus Cognitive Sparing or Hippocampal Avoidance Whole Brain RadioTherapy for Multiple Brain Metastases (SMART): A Phase II Randomized Trial

The goal of this phase II randomized trial is to determine if Stereotactic Radiosurgery (SRS) or Cognitive Sparing WBRT (CS-WBRT) better preserves neurocognitive function than standard Hippocampal Avoidance WBRT (HA-WBRT) in patients with multiple brain metastases ( $\ge6$ lesions).

The main questions it aims to answer are:

• Which treatment best preserves cognitive function (memory and executive tasks) at 6 months post-intervention?
• Can sparing the left hippocampus and corpus callosum (CS-WBRT) or using focal SRS reduce cognitive decline compared to bilateral sparing? Comparison Groups

Researchers will compare three arms to evaluate their impact on cognition and disease control:

• Arm A (SRS): Focal high-dose radiation (15-20 Gy in 1 fraction) to intracranial lesions.
• Arm B (CS-WBRT): Whole-brain radiation (30 Gy in 10 fractions) sparing the left hippocampus and corpus callosum plus Memantine.
• Arm C (HA-WBRT): Whole-brain radiation (30 Gy in 10 fractions) with bilateral hippocampal avoidance plus Memantine.

Participant Tasks

Participants will:

• Complete neurocognitive and neuropsychological tests (HVLT-R, TMT, COWAT, CANTAB) at baseline and follow-up.
• Undergo contrast-enhanced brain MRI for planning and tracking tumor progression.
• Take Memantine HCL daily for 24 weeks if assigned to the WBRT arms (B or C).
• Provide blood samples for biomarker and genetic analysis (e.g., APOE, Tau).
• Undergo olfactory function testing and complete quality-of-life questionnaires.

Study Overview

• Status: Not yet recruiting
• Conditions: Brain Metastases From Solid Tumors
• Intervention / Treatment: Radiation: SRS; Radiation: CS-WBRT; Radiation: HA-WBRT

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Wen-Chi Yang, MD, PhD; Phone Number: +886912545812; Email: claireds23@ntuh.gov.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
2. Patients with brain metastasis outside a 5-mm margin around either hippocampus or corpus callosum on gadolinium contrast-enhanced MRI obtained within 30 days prior to registration
3. Patients with 6 or more active or progressive brain metastases that have not been treated by radiotherapy or radiosurgery
4. No evidence of diffuse leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration
5. Age ≥ 18 years
6. Karnofsky Performance Status ≥ 60%
7. Life expectancy ≥ 6 months.
8. Women of childbearing potential and male participants must practice adequate contraception
9. Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

Exclusion Criteria:

1. Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s)
2. Clinical diagnosis of symptomatic leptomeningeal metastsases
3. Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia

4. Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:

   1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
   2. Transmural myocardial infarction ≤ 6 months prior to registration
   3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
   4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
   5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
   6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   7. Uncontrolled psychiatric disorder
5. Will receive any other investigation agent or chemotherapy during cranial radiotherapy or radiosurgery
6. Current use of Memantine HCL or Allergy to Memantine HCL
7. Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic
8. Pregnant or breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SRS	Radiation: SRS; Focal high-dose radiation (15-20 Gy in 1 fraction) to intracranial lesions
Experimental: CS-WBRT	Radiation: CS-WBRT; Conformal Whole Brain Radiotherapy 3000 cGy in 10 fractions with Left Hippocampal Avoidance & Corpus Callosum Sparing using RapidArc
Active Comparator: HA-WBRT	Radiation: HA-WBRT; Conformal Whole Brain Radiotherapy 3000 cGy in 10 fractions with Bilateral Hippocampal Avoidance using RapidArc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preservation in neurocognitive function at 6 months after the start of brain radiotherapy for patients with multiple brain metastases	The primary endpoint is defined as the z-scores of changes in HVLT-R memory score, and CANTAB® tasks at 6 months after the start of cranial radiotherapy or radiosurgery for multiple brain metastases. Investigators hypothesize that at least one of the three treatment arms will outperform the others in preserving neurocognitive function at 6 months	From enrollment to 6 months after the start of brain radiotherapy

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2031

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 29, 2026
• First Posted (Actual): April 1, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Stereotactic Radiosurgery; Brain metastases; Hippocampal Avoidance Whole Brain Radiotherapy; Cognitive Preservation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Neoplasms
• Other Study ID Numbers: 202510164MIFD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No