Neoplasms

Nervous System Diseases

All Conditions

Behaviors and Mental Disorders

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Quality of Life

Patients receive proton Radio(chemo)therapy according to clinical standard. Proton Treatment is indicated BEFORE inclusion into the trial ans is not part of the trial. Neurological status and neurocognitive testing on core executive functions (inhibition, working memory, cognitive flexibility) and Quality of life measurements are performed regularely during follow-up using standardized KINDL® questionnaires for general quality of life and specific for oncologic diseases. In addition to the treatment parameters of the radio(chemo)therapy protocol, further radiation doses to brain substructures and organs at risk are documented.

Patients are included AFTER surgery of their brain tumour and receive no radiotherapy due to their disease (i.e. according to clinical standard). This Treatment is not part of the trial, but stratifies the Patient in this second Group.

Neurological status and neurocognitive testing on core executive functions (inhibition, working memory, cognitive flexibility) and Quality of life measurements are performed regularely during follow-up using standardized KINDL® questionnaires for general quality of life and specific for oncologic diseases.

Healthy kids are recruited as Standard Group.

Neurological status and neurocognitive testing on core executive functions (inhibition, working memory, cognitive flexibility) and Quality of life measurements are performed regularely using standardized KINDL® questionnaires for general quality of life and specific for oncologic diseases.

Mechthild Krause, Prof. Dr.

Christian Beste, Prof. Dr.

Maja von der Hagen, Prof. Dr.

Brain tumors are the second most frequent malignant diseases in children and adolescents. In the study the short and medium term consequences of proton therapy on cognitive processes in particular on executive functions in pediatric patients shall be highlighted/analysed/evalutated. In a second step, these results are to be compared with

1. a group of children and adolescents who had only /exclusively had operative therapy and
2. with a healthy control group. Thus, the extent to which these treatment options differ in terms of their short and medium-term effect is assessed. Methods of neurocognitive/neurophysiology brain research approaches are applied that may potentially visualize even small / subtle changes in mental activities/neurocognitive function. Therefore the effects of treatment can be evaluated and the neuropsychological outcome of children and adolescents with brain tumors can be improved.

Radio(chemo)therapy with protons is conducted according to current treatment standards or, for patients participating in a clinical intervention study, according to the study protocols of the GPOH. Only patients with prescribed radiation doses \> 40 Gy (RBE) will be included. Treatment planning, the target volume and radiotherapy will be performed according to the current treatment standards. For patients participating in a clinical intervention study, radiotherapy is corresponding to study protocol of the GPOH. Risk organs (e.g. brain stem, chiasma, optic nerves, gll. Lacrimals, lenses, inner ears and spine) are contoured and the radiation doses for these organs are limited according to institutional guidelines. Radiotherapy is performed according to guidelines, i.e. 5 days a week for 4-6 weeks, usually on an outpatient basis.

Neurocognitive Function After Proton Therapy in Children and Adolescents

Neurocognitive Function /Executive Functions After Proton Therapy in Children and Adolescents.

Neurophysiological processes are examined while subjects perform the cognitive tests.

QoL Parameters are measured and reported using KINDL® questionnaires for general quality of life and specific for oncologic diseases (also KINDL®). Scales for QoL items are 0-100 (with 100 being the Optimum, i.e. lower values indicating worse outcome). Evaluation is performed according to the standard published with the validated questionnaires (https://www.kindl.org/deutsch/fragebögen/)

physical doses to substructures of the brain are collected and correlated with neurophysiological outcome measures

Gert und Susanna Mayer Stiftung

Technische Universität Dresden

Head and Neck Neoplasms

Anti-Infective Agents

Central Nervous System Depressants

All Drugs and Chemicals

Ethanol

The performance-based measures will be administered with a total completion time estimated to be 90 minutes. The neurocognitive battery is similar in content and duration to multiple previous and ongoing studies being conducted by the Neurocognitive Research Lab.

Baseline only: WRAT Reading Test, WMS-IV Logical Memory Subtest, Hopkins Verbal Learning Test (HVLT), Oral Trailmaking - Part A and B, NAB Digit Span, Category Fluency Test, Oral Symbol Digit Modalities Test, Brief Test of Attention, FAS - Controlled Oral Word Association Test (COWAT), Verbal Naming, Enformia Cogsuite Battery

Neurocognitive Tests

Sociodemographics, Computerized Cognitive Training Programs Questionnaire, CDC Behavioral Risk Factor (Smoking Assessment), Alcohol Consumption CDC, Current Health Rating (KPS), OARS Physical Health section, COVID Medical History, Hospital Anxiety and Depression Scale (HADS), Fatigue Symptom Inventory (FSI), Functional Assessment of Cancer Therapy-General (FACT-G V4), Functional Assessment of Cancer Therapy-Cognition (FACT-Cog V3), Sensory Gating Inventory (SGI)

Questionnaires

Jonine Bernstein, PhD

The researchers are doing this study to collect more information about if, and how, neurocognitive function may be affected in people being treated with radiation therapy for head and neck cancer. Part of this study is to see if patients diagnosed with head and neck cancer who are undergoing radiation therapy are able to complete neurocognitive testing and questionnaires at 3 times over a period of 1 year.

A Study of Neurocognitive Tests and Questionnaires for People With Head and Neck Cancer Who Are Undergoing Radiation Therapy

Pilot Study of Radiation-Associated Neurocognitive Function Among Head and Neck Cancer Patients

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Memorial Sloan Kettering Cancer Center

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Neoplastic Processes

Conventional whole-brain radiotherapy for brain metastases from breast cancer with dose of 37.5 Gy in 15 fractions.

Hippocampal-sparing whole brain radiotherapy is performed using modern intensity-modulated radiotherapy (IMRT) technique to avoid conformally the hippocampal neural stem-cell structure during WBRT. Prescription dose is 37.5 Gy in 15 fractions.

whole brain radiotherapy

Zheng Jiang

Bing Sun, M.D.

Based on evidence that radiation-induced damage to the hippocampus plays a considerable role in neurocognitive decline after cranial irradiation, hippocampal-sparing whole brain radiation therapy (HS-WBRT) has been proposed. This study will investigate the neurocognitive function and prognosis between HS-WBRT and conventional WBRT for the treatment of brain metastases from breast cancer.

Hippocampal-sparing Whole Brain Radiotherapy for Brain Metastases From Breast Cancer

Whole Brain Irradiation With Hippocampal Sparing for Brain Metastases From Breast Cancer: Neurocognitive Function and Prognosis Analysis

delayed recall using Hopkins Verbal Learning Test

Affiliated Hospital to Academy of Military Medical Sciences

Anti-Dyskinesia Agents

Cardiotonic Agents

Memantine

Antiparkinson Agents

Dopamine

Dopamine Agents

Neurotransmitter Agents

Excitatory Amino Acid Antagonists

Conformal whole brain radiotherapy with unilateral hippocampal avoidance and Concurrent use of Memantine HCL

Conformal whole brain radiotherapy with bilateral hippocampal avoidance and Concurrent use of Memantine HCL

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Unilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Bilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance

Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks

Memantine Hydrochloride

Feng-Ming Hsu, MD, PhD

Feng-Ming Hsu, MD

Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness.

Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27\~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, more than one- third of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis.

The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the result of phase III randomized trials suggested hippocampal avoidance plus Memantine significantly reduce the risk of neurocognitive impairment at 6 months from 68.2% in control arm with standard WBRT to 59.5% in experimental arm. In the investigator's prior investigation, patients received conformal WBRT with bilateral hippocampal avoidance also had significant less declines in verbal memory at 6 months.

Previous studies showed the right and left hippocampus exert different neurocognitive functions. Several retrospective studies also demonstrated that the radiation dose to the left hippocampus is more related to neurocognitive impairment. Planning study and investigation showed that by avoiding the left hippocampus alone, the radiation dose to the spared unilateral hippocampus is further decreased. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with bilateral or unilateral hippocampal avoidance and memantine.

Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases

Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With Bilateral or Unilateral Hippocampal Avoidance Plus Memantine for Brain Metastases: A Phase II Single Blind Randomized Trial

Number of participants with Genomic risk of neurocognitive impairment after WBRT

Decline in Hopkins Verbal Learning Test-Revised (HVLT-R) memory score (sum of total recall and recognition index) from baseline to 6 months after the start of conformal whole brain radiotherapy (WBRT) with bilateral or unilateral hippocampal avoidance for multiple brain metastases. HVLT-R Total recall raw scores ranged from 0 to 36, recognition index ranged from 0 to 12. The higher the score indicated better short term memory preservation

Evaluate neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R) with Total recall score (range from 0 to 36), delayed recall score (range from 0 to 12) and recognition index (range from 0 to 12). The higher the score indicated better short term memory preservation.

Evaluate neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A \& B. TMT-A and B tested the executive function documented with time needed for complete test with no upper limit of range. The longer the time needed, the worse executive function patients preserved.

Evaluate neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test. Patients are given one phoneme at a time and instructed to say aloud as many words beginning with that phoneme as they could within 1 minute, for a total of three phonemes in 3 minutes. The more the words patients able to say in limit time, the better outcome presented.

EORTC Quality of Life-Core 30 questionnaire module (at question 1 to 27, range from 1 to 4; at question 29 and 30, range from 1 to 7) Quality of Life questionnaire-Brain.

Function Assessment Cancer Therapy for patients with Cognitive function issue

Common Toxicity Criteria for Adverse Events version 4

Number of participant with intracranial progression on MRI of brain

National Taiwan University Hospital

Conformal whole brain radiotherapy with hippocampal avoidance

Conformal whole brain radiotherapy without hippocampal avoidance

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Hippocampal avoidance WBRT

Conformal WBRT

Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness.

Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27\~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, 33% of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis.

The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the preliminary result of Radiation Therapy Oncology Group (RTOG) 0933 suggested hippocampal avoidance significant reduce the mean relative decline at 4 months from 30% in historical cohort with WBRT to 7% in experimental cohort.

Previous studies showed brain structures other than hippocampus are also associated with radiation-induced decline in neurocognitive function. There is presence of placebo effect for interventions seeking improvement in neurocognitive function. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with or without hippocampal avoidance.

This is a single institutional, randomized phase II study to assess the neurocognitive outcome of conformal WBRT with or without hippocampal avoidance in patients with multiple brain metastases.

Patients will be randomly assigned 1:1 to receive conformal WBRT with or without hippocampal avoidance using permuted blocks within strata that are defined by Graded Prognostic Assessment (GPA) score and baseline neurocognitive status. All patients and co-investigators except the principal investigator and attending radiation oncologists will be blinded for treatment groups.

The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks. Breaks in treatment should be minimized.

Hippocampal Avoidance WBRT:

The dose is prescribed such as 90% of cranial content PTV is covered by the prescription dose.

Maximum dose to 2% of the PTV (D2%) is 37.5 Gy, and minimum dose to 98% of the PTV (D98%) is 25 Gy. Minimum dose to 100% of the hippocampal avoidance regions is 10 Gy, and dose to any point within the hippocampal avoidance regions cannot exceed 17 Gy.

Conformal WBRT:

The dose is prescribed such as 95% of cranial content PTV is covered by the prescription dose.

Maximum dose to 1% of the PTV (D1%) is 36 Gy, and minimum dose to 99% of the PTV (D99%) is 27 Gy.

Follow-up \& Assessment

Side effect evaluation:

* Acute (≤ 90 days from WBRT start) toxicities (CTCAE ver.4)
* Late (\> 90 days from WBRT start) toxicities (CTCAE ver.4)

Functional evaluation: at baseline, 2-, 4- ,and 6-month, every 3 months for 12 months until intracranial disease progression or death after WBRT

* Neurocognitive function
* Self-reported cognitive functioning (two items from EORTC Quality of Life Questionnaire-C30 Taiwan)
* Health-related quality of life specific for brain neoplasms (EORTC Quality of Life Questionnaire-Brain Neoplasm Taiwan)

Efficacy evaluation:

* Follow-up brain MRI at 4-, 9- ,and 12-month until intracranial disease progression, or death.
* Overall survival

Neurocognitive Outcome of Conformal WBRT w/wo Hippocampal Avoidance for Brain Metastases

Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With or Without Hippocampal Avoidance for Brain Metastases: A Phase II Single Blind Randomized Trial

Decline in Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score from baseline to 4 months after the start of conformal whole brain radiotherapy with or without hippocampal avoidance for brain metastases

Evaluate neurocognitive function by a standardized neurocognitive battery (HVTL-R, Trail Making Test Part A \& B, forward \& backward Digit Span).

EORTC Quality of Life-Core 30 questionnaire module and Quality of Life questionnaire -brain

30 Gy in 10 fractions hippocampal sparing whole brain radiotherapy will be administered by Helical Tomotherapy, IMRT, or VMAT

30 Gy in 10 fractions conventional whole brain radiotherapy will be administered

Hippocampal sparing whole brain radiotherapy

Conventional whole brain radiotherapy

Gillian Whitfield, MA,MB BS,PhD

The purpose of this study is to evaluate whether sparing the hippocampi during whole brain radiotherapy following neurosurgery or stereotactic radiosurgery in patients with brain metastases from a systemic tumour helps preserve brain function.

Hippocampal Sparing Whole Brain Radiotherapy vs Conventional Whole Brain Radiotherapy in Patients With Brain Metastases

A Randomized Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1-10 Brain Metastases

A decline in total recall will be assessed as being clinically significant if there is at least a 5 point decrease in total recall score at 4 months, compared to baseline \[Jacobson 1991, Brandt 1998\]

NCF, using a 30-60 min test battery (Memory - HVLT-R, Wechsler Memory Scale (logical memory subtest), Rey figure test, Wechsler digit span; Attention - Test of Everyday Attention (map search subtest), Trail Making Test (Parts A and B); Language - Graded Naming Test); this may be revised in the light of forthcoming recommendations on NCF assessment in brain metastases trials by the RANO (Revised Assessment in Neuro-oncology) working party

Quality of life will be assessed using EORTC QLQ C30 and BN20 and EuroQol EQ-5D questionnaires

The duration of functional independence will be assessed as the time for which the Karnofsky Performance Status ≥ 70

Incidence of metastases within the perihippocampal region, local control, and intracranial control will be assessed on the basis of MRI imaging

Date of death will be determined from the medical records, or from the GP

Steroid and antiepileptic medication use will be recorded in patient diaries and assessed at clinic visits

Acute and late side effects of radiotherapy will be assessed using NCI CTCAE scale v4.03

Cancer Research UK

The Brain Tumour Charity

University College, London

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Neuroendocrine Tumor

Neuroepithelioma

Patients will receive WBRT after local treatment. A minimum of 30 Gy in 10 fractions given as one fraction per day within 4 weeks of randomisation

A minimum of 30 Gy in 10 fractions given as one fraction per day within 4 weeks of randomisation

WBRT

Gerald Fogarty, BSc, MBBS

People with brain metastases from melanoma are offered different treatment options after local treatment of their brain metastases via surgery or stereotactic irradiation. Depending on the treating institution and the clinician involved a patient may or may not be offered whole brain radiotherapy (WBRT) after their brain metastases are excised or treated with stereotactic irradiation. This trial seeks to determine if WBRT reduces the spread of brain metastases and lengthens the time to recurrence. The trial also examines the effect of WBRT on quality of life and brain functions such as memory, speech and concentration. Participants will be randomised after local treatment of their brain metastases to either WBRT or observation. 220 people will be recruited from sites in Australia, Norway, the UK, the US and other international sites.

Whole Brain Radiotherapy Following Local Treatment of Intracranial Metastases of Melanoma

Whole Brain Radiotherapy Following Local Treatment of Intracranial Metastases of Melanoma - A Randomised Phase III Trial

Trans Tasman Radiation Oncology Group

University of Oxford

Melanoma and Skin Cancer Trials Limited

Patients with brain metastases outside a 5-mm margin around either hippocampus and are eligible to this study will receive hippocampal avoidance whole brain radiotherapy 30 gray (Gy) in 10 fractions. The primary endpoint is Wechsler Memory Scale (Chinese) and cognitive abilities screening instrument (CASI) at 4 months.

Planning target volume(PTV) for whole brain is Whole brain parenchyma plus2mm margin excluding metastases and HA region, 30Gy in 10 fractions will be delivered to PTVwhole brain. Bilateral Hippocampus will be contoured according to Radiation Therapy Oncology Group 0933 and hippocampal avoidance region is Hippocampi + 5mm margin. According to Radiation Therapy Oncology Group 0933 trial, dose to 100% of the hippocampus could not exceed 9 Gy, and maximal hippocampal dose could not exceed 16 Gy; dose to 100% of the hippocampus exceeding 10 Gy

Hippocampal avoidance whole brain radiotherapy

Pen-Tzu Fang, MD

Fang Pen-Tzu, MD

The study aimed to investigate the memory preservation and neurocognitive function protection of hippocampal avoidance whole brain radiotherapy (HA-WBRT) among people who speak Mandarin Chinese or Taiwanese.

Brain metastasis is very common, about 30% incidence rate for all patients with a diagnosis of cancer. The rising incidence of brain metastasis is most likely due to recent advances in systemic therapy, and use of magnetic resonance imaging (MRI). The most common primary site is the lung followed by breast. One of the standard treatments is whole brain radiotherapy; it can prolong the decline of neurocognitive function and improve quality of life. However, it can also cause decline in neurocognitive function as a late sequela. Memory impairment is the main cognitive function that affected by radiotherapy, and the neuronal stem cells located at hippocampal subgranular zone are highly sensitive to radiotherapy. There have been large randomized trials confirming that by HA-WBRT, the neurocognitive function decline can be reclaimed. In Taiwan, HA-WBRT is a popular and emerging treatment. However, not much study focused on its effects on neurocognitive function. The study is aimed to objectively investigate the memory preservation and neurocognitive function protection of HA-WBRT in people speaking Mandarin Chinese or Taiwanese by utilizing neurocognitive function test and QoL questionnaire.

Hippocampal avoidance -whole brain radiotherapy(HA-WBRT), which delivers radiation to whole brain and moreover, to reduce mean dose to hippocampal neural stem-cell compartment to minimize the neurocognitive function impairment

Memory Preservation of Hippocampal Avoidance Whole Brain Radiotherapy

The Memory Preservation Study of Whole Brain Radiotherapy With Hippocampal Avoidance for Patients With Brain Metastases

The memory battery is using Wechsler Memory Scale (Chinese), including Logical Memory I \& II, Word Lists Ⅰ \& II, Faces Ⅰ and spatial span.

General cognitive function are tested using cognitive abilities screening instrument, CASI for screening and to test cognitive function as a whole.

Quality of life are assessed using The Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire

Kaohsiung Medical University Chung-Ho Memorial Hospital

This is a single arm phase II study where enrolled subjects will receive intracranial SRS will performed identically to standard of care, except for implementing additional imaging techniques and software for additional regional avoidance for cognitive sparing (specifically sparing white matter and the bilateral hippocampus)

In this proposal, the investigators introduce advanced diffusion and volumetric imaging techniques along with innovative, automated image parcellation methods to identify critical brain regions, incorporate into cognitive-sparing SRS, and analyze biomarkers of radiation response. This work will advance the investigators' understanding of neurocognitive changes after brain SRS and help create interventions that preserve cognitive-function in brain metastases patients.

Cognitive Sparing Brain Stereotactic Radiosurgery (SRS)

Lara J Rose

Jona Hattangadi-Gluth, MD

Background: Brain metastases affect one third of adult cancer patients. Stereotactic radiosurgery (SRS) is standard of care for patients with limited brain metastases. Yet most patients will experience post-treatment cognitive decline given the potential for high doses to eloquent white matter and the hippocampus.

Objective/Hypothesis: The investigator's team has developed innovative, robust imaging methods and automated segmentation techniques to identify critical white-matter tracts and the hippocampus using advanced diffusion tensor imaging (DTI) and volumetric imaging. These novel imaging techniques also allow us to directly and non-invasively measure microstructural changes after RT to critical brain structures in vivo. The investigators will use these advanced imaging technologies in a prospective trial of cognitive-sparing brain SRS for brain metastases patients.

Specific Aims: 1: To evaluate whether relative sparing of eloquent white matter tracts (critical for memory, language, attention, and executive functioning) and hippocampi from high doses during brain SRS results in improved 3-month post-SRS cognitive performance relative to historical controls in patients with 1 to 3 brain metastases. 2: To measure longitudinal trends in white matter damage (using DTI) and hippocampal atrophy (using volumetric change) among patients receiving cognitive-sparing brain SRS and correlate these imaging biomarkers with domain-specific cognitive outcomes.

Study Design: The investigators will prospectively enroll 60 adult patients with 1-3 brain metastases who are eligible for brain SRS and MRI. Patients will undergo MRI with DTI and 3D volumetric imaging at baseline (pre-SRS) and 1 month, 3 months, and 6 months afterwards. White matter and hippocampal segmentation will be performed and critical regions integrated into cognitive-sparing brain SRS planning with automated knowledge-based optimization. Cognitive-sparing dose constraints are derived from previous data. A well-established, validated battery of neurocognitive tests will be performed at baseline and 3 months post-SRS. Cognitive deterioration rate will be compared between the current trial and historical controls and linear regression used to analyze patient, tumor, and treatment related predictors of cognitive decline. Statistical modeling will be used to analyze changes in imaging biomarkers as a function of time and radiation dose, and these changes will be tested for association with domain-specific cognitive tests. Spatial sensitivity to RT dose across white matter tracts will be analyzed.

Study patients will undergo MR imaging with DTI and 3D volumetric imaging at baseline (pre-SRS), and 1 month, 3 months, and 6 months afterwards. This regimen of post-SRS MR imaging is clinical standard of care. Segmentation of critical white matter and hippocampal volumes will be performed pre-SRS for use in brain SRS planning. Formal neurocognitive assessments will be performed at baseline and 3 months post-SRS.

UCSD Image-Guided Cognitive-Sparing Radiosurgery for Brain Metastases

UCSD Image-Guided Cognitive-Sparing Radiosurgery for Brain Metastases: Avoidance of Eloquent White Matter and Hippocampal Regions

To evaluate the change from baseline to 3-month post-SRS verbal memory performance when performing relative sparing of eloquent white matter tracts and hippocampi from high doses during brain SRS in patients with 1 to 3 brain metastases. Verbal memory outcomes and measurements include: Hopkins Verbal Learning Test-Revised (HVLT-R)-Immediate, Delayed Recall. Scale of scores is 0-36 for Immediate, 0-12 for Delayed. For both tests, higher scores indicate better performance.

To evaluate the change from baseline to 3-month post-SRS executive functioning performance when performing relative sparing of eloquent white matter tracts and hippocampi from high doses during brain SRS in patients with 1 to 3 brain metastases. Executive functioning outcomes and measurements include: Controlled Oral Word Association Test (COWA): letter fluency, Trail Making Test Part B (TMT-B).

Scale of scores is:

Controlled Oral Word Association Test (COWA): letter fluency: 0- no upper limit. Higher score indicates better performance Trail Making Test Part B (TMT-B): 0-240. Higher score indicates poorer performance

To evaluate the change from baseline to 3-month post-SRS Attention/Processing Speed performance when performing relative sparing of eloquent white matter tracts and hippocampi from high doses during brain SRS in patients with 1 to 3 brain metastases. Attention/Processing Speed outcomes and measurements include: Trail Making Test Part A (TMT-A)

Scale of scores is:

Trail Making Test Part A (TMT-A): 0-240. Higher score indicates poorer performance

To evaluate the change from baseline to 3-month post-SRS Language performance when performing relative sparing of eloquent white matter tracts and hippocampi from high doses during brain SRS in patients with 1 to 3 brain metastases. Language outcomes and measurements include: Boston Naming Test (BNT), Controlled Oral Word Association Test (COWA): category fluency

Scale of scores is:

Boston Naming Test (BNT): 0-60 Controlled Oral Word Association Test (COWA): category fluency: 0-no upper limit For both tests, higher score indicates better performance.

To measure longitudinal changes in FA (unitless index between 0 and 1) from DTI imaging

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neurocognitive Function After Proton Therapy in Children and Adolescents	NCT04066465	Primary Brain T...		8 Years - 18 Years	Technische Universität Dresden
A Study of Neurocognitive Tests and Questionnaires for People With Head and Neck Cancer Who Are Undergoing Radiation Therapy	NCT05207098	Head and Neck C...	Neurocognitive ... Questionnaires	18 Years - 89 Years	Memorial Sloan Kettering Cancer Center
Hippocampal-sparing Whole Brain Radiotherapy for Brain Metastases From Breast Cancer	NCT03002532	Breast Cancer M... Brain Metastase...	whole brain rad...	18 Years - 75 Years	Affiliated Hospital to Academy of Military Medical Sciences
Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases	NCT04801342	Metastatic Mali...	Conformal Whole... Conformal Whole... Memantine Hydro...	20 Years -	National Taiwan University Hospital
Neurocognitive Outcome of Conformal WBRT w/wo Hippocampal Avoidance for Brain Metastases	NCT02393131	Metastatic Mali...	Hippocampal avo... Conformal WBRT	20 Years -	National Taiwan University Hospital
Hippocampal Sparing Whole Brain Radiotherapy vs Conventional Whole Brain Radiotherapy in Patients With Brain Metastases	NCT02147028	Brain Metastase...	Hippocampal spa... Conventional wh...	16 Years -	University College, London
Whole Brain Radiotherapy Following Local Treatment of Intracranial Metastases of Melanoma	NCT01503827	Metastatic Mela...	WBRT	18 Years -	Melanoma and Skin Cancer Trials Limited
Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases	NCT04801342	Metastatic Mali...	Conformal Whole... Conformal Whole... Memantine Hydro...	20 Years -	National Taiwan University Hospital
Memory Preservation of Hippocampal Avoidance Whole Brain Radiotherapy	NCT03247127	Brain Metastase... Neurocognitive ...	Hippocampal avo...	20 Years - 80 Years	Kaohsiung Medical University Chung-Ho Memorial Hospital
UCSD Image-Guided Cognitive-Sparing Radiosurgery for Brain Metastases	NCT04343157	Brain Metastase... Neurocognitive ... Cancer	Cognitive Spari...	18 Years -	University of California, San Diego

Spots Global Cancer Trial Database for neurocognitive function