Mouth and Tooth Diseases

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Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Quality of Life

Patients with five or more brain metastasis assigned by randomization to Stereotactic RadioSurgery (SRS) or Stereotactic Body RadioTherapy (SBRT) will be treated with a highly-conformal metastasis-directed single dose between 15 and 24 Gy or fractionated dose (e.g. 27 Gy in 3 fractions), respectively, depending on lesion size, while sparing clinically negative brain. The treatment will be delivered using five non-coplanar arcs and a mono-isocentric technique.

Patients with five or more brain metastasis assigned by randomization to Whole Brain Irradiation (WBI) will be treated using a 3D-Conformal RadioTherapy technique for a uniform dose delivery of 30 Gy in 10 daily/fractions to the target, that is entire brain.

To treat only brain metastasis identified through Magnetic Resonance imaging by means of stereotactic radiotherapy (experimental intervention) to determine if sparing of clinically uninvolved brain implies a better neurocognitive performance, quality of life and level of autonomy in activities of daily living respect to Whole Brain Irradiation (active comparator).

Stereotactic RadioTherapy

To irradiate the entire brain, site of at least 5 parenchymal metastasis.

Whole Brain Irradiation

Gianluca Ferini

Irene R. Cravagno, Chief Radiation Oncology Unit

Anna Viola, Radiation Oncologist

Gianluca Ferini, Chief Radiation Oncology Unit

Vito Valenti

Antonella Tripoli

Silvana Parisi

Stefano Pergolizzi

Antonio Pontoriero

Alberto Cacciola

Sara Lillo

Gianluca Mortellaro

Giuseppe Ferrera

This work aims to evaluate neurocognitive performance, daily activity and quality of life and local control among patients with brain metastasis (MBM) ≥ 5 due to solid tumors treated with Stereotactic RadioSurgery (SRS) or Whole Brain RadioTherapy (WBRT). This multicentric randomised controlled trial will be conducted at the Fondazione IOM (Viagrande) in collaboration with REM (Viagrande), Hospital G. Martino (Messina) and Hospital Civico ARNAS (Palermo). It will involve, within 5 years starting from 15 September 2020, the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy \> 3 months, histological confirmation of primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) of 20/30, Barthel Activities of Daily Living score 90/100, to be subjected to SRS on each brain lesion by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBRT (control arm). The primary endpoints are neurocognitive performance, quality of life and autonomy in daily-life activities variations, the first one assessed by Moca Score and Hopkins Verbal Learning Test - Revised, the second one through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL) and Brain Neoplasm (BN-20) questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatments frequency, acute and late toxicities, KPS decrease. It will be considered significant a statistical difference of at least 29% between the two arms (statistical power of 80% with a significance level of 95%). This trial has been approved by the local ethics committee on July 7th 2020 (record 70). Several studies debate what is the predominant factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiotherapy, especially if extended to the entire brain, or intracranial disease progression? Answer to this question may come from current opportunity, thanks to recent technological advancement, to treat, with significant time savings, improved patient comfort and at the same time minimizing the dose to healthy brain tissue, Multiple Brain Metastasis simultaneously, otherwise attackable only by panencephalic irradiation. The pursuit of a local control rate comparable to that obtainable with WBRT remains the fundamental prerequisite for the aforementioned related assessments.

WHOle Brain Irradiation or STEreotactic Radiosurgery for Five or More Brain Metastases (WHOBI-STER)

WHOle Brain Irradiation and STEreotactic Radiosurgery for Five or More Brain Metastases (WHOBI-STER): a Prospective Comparative Study of Neurocognitive Outcomes, Level of Autonomy in Daily Activities and Quality of Life

To assess how neurocognitive performance changes after SRS/SBRT compared to WBI

To assess how level of autonomy in activities of daily living changes after SRS/SBRT compared to WBI

To assess how quality of life changes after SRS/SBRT compared to WBI

Time between treatment and cerebral disease progression detected through Magnetic Resonance imaging

Time from the first day of treatment to exitus

Difference in needing further subsequent radiotherapy treatment between SRS/SBRT and WBI arms

Toxicities registered within three months from treatment

Toxicities registered after three months from treatment

Evaluation of how patient's performance status modifies after treatment

University of Messina

University of Palermo

Mediterranean Institute of Oncology

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Peripheral Nervous System Neoplasms

Neurofibromatosis

Neurofibromatosis Type 1

Parents in the intervention arm will receive one single-session intervention one month after completion of baseline measures. They will also complete a feasibility exit interview one month after completion of their data collection period (i.e., at 7 months).

Families in the control arm will complete measures at the exact same timepoints as those in the intervention arm but will not receive the single session intervention and will not complete the feasibility exit interview. They will receive the same information as the intervention arm via an education manual at the completion of their data collection period.

The purpose of the intervention feedback session will be twofold: 1) to provide the results of the previous assessment, and 2) to provide general psychoeducation on psychological and neurocognitive functioning and tailored cognitive and behavioral interventions based on the results in order to reduce the impact of psychological and neurocognitive deficits.

OPTIMAL-SSI

Jennifer M Rohan, PhD

Children with neurofibromatosis are more likely to have difficulties related to their psychological and neurocognitive functioning (e.g., more likely to have depression, have social difficulties, be diagnosed with ADHD). The purpose of this randomized control study is to determine how effective and useful this study's single session intervention can be in improving psychological and neurocognitive functioning. Enrolled families will consist of one parent/guardian and child. Parents and patients will complete questionnaires and objective tests at baseline, 3 months, and 6 months. Families randomized to the intervention arm will be provided with one single session intervention at Month 1 to learn about their child's testing results and receive psychoeducation and recommendations related to psychological and neurocognitive functioning.

Neurofibromatosis type 1 (NF1) is a chronic illness that is typically diagnosed during childhood and is associated with a variety of medical, psychological, and neurocognitive symptoms. NF1 is a genetic disorder, affecting about 1 in 3,000 people throughout the world. Diagnosis usually occurs in childhood and is characterized by the presence of several markers, including, but not limited to: multiple café au lait (light brown) skin spots, neurofibromas (small benign growths) on or under the skin, optic pathway gliomas, bone dysplasia, and freckling in the armpits or groin. Aside from its medical manifestations, NF1 also is associated with psychological impairment and a wide variety of neurocognitive deficits. In comparison to healthy peers and the general population, children and adolescents with NF1 have been found to have more social difficulties (e.g., more peer conflicts, fewer friends), internalizing symptoms (e.g., anxiety, depression, withdrawal), externalizing symptoms (e.g., sub-threshold or clinical symptoms consistent with ADHD such as inattention, hyperactivity, impulsivity), sleep difficulties; and worse quality of life. Additionally, while the vast majority of children with NF1 have intelligence in the average to low average range, neurocognitive deficits have been found in a range of domains including: linguistic development, verbal concept formation, reasoning, visuospatial skills, motor skills, executive function (e.g., cognitive flexibility, working memory, inhibitory control), academic achievement (e.g., reading/spelling, math), and attention. There is further support that early onset of mental health problems are associated with both future mental health problems and poorer functional outcomes in adulthood (e.g., unemployment, lower earnings, lower academic attainment).

Children with NF are more likely to be diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) than their healthy counterparts. Early detection, prevention, and intervention of psychological and neurocognitive risk may serve as a protective factor for later adverse outcomes. A meta-analysis of 175 research studies worldwide on ADHD in children ages 18 and younger found an overall pooled estimate of 7.2% of children and adolescents diagnosed with ADHD within the general population; however, ADHD is over-represented within the NF1 population, with an estimated 31 to 50% of children meeting diagnostic criteria for ADHD. Although there is limited research investigating the longitudinal impact of ADHD and NF on pediatric patients, longitudinal studies of children with ADHD document deficits in multiple domains including lower levels of education, poorer social functioning, and worse occupational outcomes. Therefore, children with comorbid diagnoses of both NF1 and ADHD or even those NF patients with sub-threshold symptoms of ADHD are likely to be at an increased risk for functional deficits later in life.

Given the general current demand for psychological services, there is a great need for brief, problem-focused psychological interventions targeting psychological and neurocognitive functioning in NF. Emerging data indicate a significant increase in mental health needs as a result of the COVID-19 pandemic, which is consistent with previous large-scale disasters and pandemics. This is a significant healthcare crisis given that prior to the pandemic in the United States, more than 11.8 million people reported having unmet mental health needs. This translates to more individuals needing mental health intervention without access; and, subsequently challenges mental health providers to expand services through novel models of intervention delivery (e.g., delivering brief problem-focused interventions based on findings from standardized assessments in unconventional settings, such as, during multidisciplinary medical visits for their medical condition). One novel delivery method of psychological services is the single-session intervention (SSI), which is defined as the intentional delivery of one visit or encounter with a clinic, provider, or program. Although there is no current research investigating the feasibility and clinical effectiveness of SSI's for pediatric patients diagnosed with NF, a meta-analysis of 50 randomized control trials of SSI's for youth with psychological problems showed a significant beneficial effect (g=0.32), with greatest effect sizes for reducing anxiety (g=0.56) and conduct problems (g=0.54). Although psychoeducation-based SSI's often were found to have a small effect size, a systematic review of 13 studies conducted between 1990 and 2018 that investigated the effects of psychoeducation-based interventions on youth with ADHD showed moderate to large effects on ADHD symptom improvement as reported by parents/teachers (g=0.787), and parent/teacher and child knowledge about ADHD (g=1.037 and g=0.721, respectively).

This is a pilot feasibility study comprising a randomized controlled trial involving patients' ages 6 to 16 years (n=50) with NF. Patients will complete standardized assessment batteries and questionnaires assessing their neurocognitive, executive, and psychological functioning. The present study will yield longitudinal patterns of neurocognitive and psychosocial outcomes across the six month period, and, collect data for preliminary development of a single session intervention. In order to gather information on how patients perform and behave in different settings, patients, parents, and teachers will also complete standardized questionnaires to gather information on psychological functioning over a six month period. Given NF is associated with psychological impairment and a wide variety of neurocognitive deficits, as well as poorer functional outcomes in adulthood, there is a great need for early detection, prevention, and intervention for this vulnerable patient population.

The proposed study has the following specific aims: Aim 1) Examine the preliminary feasibility and acceptability of using a single-session intervention focused on psychoeducation and cognitive behavioral-based recommendations related to psychological, neurocognitive, and executive functioning over six months. Hypothesis 1a: We hypothesize that families will report high acceptability for the intervention. Hypothesis 1b: It is hypothesized that families assigned to the intervention group will demonstrate improvements in both objective and subjective assessments of psychological and neurocognitive symptoms, e.g., inattention and impulsivity, as well as, executive functioning when compared to those in the control group. Aim 2) Examine descriptive and longitudinal patterns of psychological and neurocognitive factors (e.g., intellectual functioning, executive functioning, attention) across six months for the sample overall, as well as, for those in the intervention and control groups. Hypothesis 2a: It is hypothesized that a similar prevalence of ADHD for patients with NF that is seen in the literature (i.e., between 31-50%) will also be observed in our sample. Hypothesis 2b: It is hypothesized that there will be individual differences in neurocognitive patterns (e.g., executive functioning, attention) across six months in pediatric patients with neurofibromatosis (NF) with significant intra-sample variability, including differences observed between those who participated in the intervention versus those who did not. We suspect that there will be subgroups of patients who have increases in attention difficulties and executive function deficits over time, another subgroup will have decreases in attention difficulties and executive function deficits over time, and a subgroup who will have stable patterns across six months.

STUDY DESIGN

Approach:

Overview of Study Design: The current design is a pilot feasibility study comprising a randomized controlled trial involving patients ages 6 to 16 years (n=50) who are diagnosed with NF and followed by the comprehensive multidisciplinary NF clinic (Dr. Wang, Director; Dr. Rohan, Co-Director). The proposed study will contribute to new knowledge by describing trajectories of neurocognitive factors over time; as well as, examining the preliminary feasibility and effectiveness of a single-session intervention on improving psychological and neurocognitive factors such as attention and executive functioning.

This comprehensive measurement approach provides a powerful tool to address important scientific and clinically relevant questions: 1) What are the patterns of neurocognitive symptom presentation in pediatric NF?; and, how do these symptoms relate to psychosocial and health outcomes over time?; 2) How might patients and families benefit from receiving psychoeducation about neurocognitive, executive, and psychological functioning in patients with NF; as well as receiving tailored recommendations based on results of neurocognitive assessments? The use of multiple measures of neurocognitive functioning (multiple reporters and objective and subjective assessment methods), standardized questionnaires, and a single-session intervention in a pilot feasibility study of patients' ages 6 to 16 years is an innovative approach that has potential clinical utility and impact. For example, identification of neurocognitive and executive functioning deficits from multiple informants may allow development of more precise interventions in different settings for children (e.g., school, home). This approach also affords the opportunity to identify risk and protective factors in living with a chronic illness and to develop preventative and therapeutic interventions that can be delivered at the point of care to minimize barriers and maximize facilitators associated across the illness trajectory for this vulnerable patient population.

Study Procedures Recruitment and Data Collection: Eligible families seen in the Pediatric NF Clinic at VCU will be invited to participate via telephone or in person (depending on timing of clinic visit). Interested patients and parents/caregivers will provide informed consent, parental permission, and assent prior to data collection. Consented participants will be randomly allocated to the intervention (n=25) or control (n=25) groups via a computerized randomization program.

Data collection will occur at four timepoints: baseline (T0), 3-months (T1), 6-months (T2), and 7-months (T3). At T0 through T2, patients will complete standardized assessment batteries for neurocognitive functioning; and, patients, parents, and teachers will complete standardized questionnaires. All measures used within the present study are well validated and can be administered longitudinally within these time intervals with acceptable test-retest reliability. At T3, families in the intervention group will complete semi-structured qualitative interviews about the feasibility, acceptability, and desirability of the intervention.

This is a pilot feasibility study comprising a randomized controlled trial involving 50 families (i.e., parent/guardian AND child ages 6 to 16 years with NF). Consented participants will be randomly allocated to the intervention (n=25) or control (n=25) arms.

Patient randomization is assigned after baseline is completed (i.e., the patient and assessor are not aware of random assignment until after the baseline is completed). The Principal Investigator and Clinical Research Coordinator will be the only ones with access to random assignments.

Intervention Effectiveness on the Neurocognitive Functioning of Children and Adolescents With Neurofibromatosis Type 1

Preliminary Feasibility and Clinical Effectiveness of a Single-Session Intervention on the Neurocognitive Functioning of Children and Adolescents With Neurofibromatosis Type 1

Intellectual function will be assessed using the Wechsler Intelligence Scale for Children (WISC) adapted to the age of the child. The child is asked to perform a variety of intellectual tasks. Overall and subscale scores are calculated by summing the number of correct answers. Higher scores indicate better intellectual function.

Neurocognitive function will be assessed using the NIH Toolbox Cognitive Test Battery (NCTB). The NCTB is a standardized set of brief measures. Tasks are completed on a tablet and scores can be evaluated separately or as composite scores. Scores are normalized with a score of 100 being average, lower scores indicating lower neurocognitive function, and higher scores indicating higher cognitive function.

Virginia Commonwealth University

Leukoaraiosis

Becky Green

Emily C Goldman

Colette J Shen, MD, PhD

Tong Zhu, PhD, DABR

Brain metastases are a source of much morbidity and mortality in adults with primary solid malignant tumors. With improvements in systemic therapy that prolong survival but have limited central nervous system penetration, patients with brain metastases are at increasing risk of developing and experiencing long-term side effects from treatment of brain metastases. The overarching goal of this study is to better understand the determinants of RT-associated changes in white and gray matter function and associated neurocognitive decline.

The proposed study aims to provide novel and useful information for clinicians, both to help predict potential neurocognitive changes following SRS, and as a possible guide for SRS treatment alteration, whether through adjustment of dose or beam arrangements in relation to white matter tracts. In this observational pilot study of 20 patients, the association between RT-associated brain injury and neurocognitive function will be quantitatively assessed longitudinally over one year following SRS. The study team hypothesizes that, over this time, (1) there will be radiation dose-dependent reductions in regional white matter tract integrity and reduction in functional connectivity in the default mode network of gray matter, (2) there will be measurable decline in neurocognitive function, and (3) there will be an association between severity of radiation-induced brain injury on MRI and magnitude of neurocognitive functional decline. This association will relate, in part, to the location(s) affected.

MRI Biomarkers for Radiation-Induced Neurocognitive Decline Following SRS of Newly Diagnosed Brain Mets

Magnetic Resonance Imaging Biomarkers for Radiation-Induced Neurocognitive Decline Following Stereotactic Radiosurgery of Newly Diagnosed Brain Metastases: An Observational Pilot Study

Correlation between magnitude of neurocognitive function decline and severity of radiation-induced brain injury

Dose-dependent reductions in white matter integrity, as quantified by Diffusion Tensor MRI (DTI)-derived measures of change in diffusivity

Dose-dependent alterations in functional connectivity, especially for the subsystems of the Default Mode Network (DMN), as measured by resting state functional MRI

Change in neurocognitive function, as measured by Delis-Kaplan testing, after SRS treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
WHOle Brain Irradiation or STEreotactic Radiosurgery for Five or More Brain Metastases (WHOBI-STER)	NCT04891471	Neurocognitive ... Quality of Life Activities of D...	Stereotactic Ra... Whole Brain Irr...	18 Years -	Mediterranean Institute of Oncology
Intervention Effectiveness on the Neurocognitive Functioning of Children and Adolescents With Neurofibromatosis Type 1	NCT05377008	Neurocognitive ... Mental Health I... Neurofibromatos...	OPTIMAL-SSI	6 Years - 16 Years	Virginia Commonwealth University
MRI Biomarkers for Radiation-Induced Neurocognitive Decline Following SRS of Newly Diagnosed Brain Mets	NCT04073966	Brain Metastase... Neurocognitive ... White Matter Al... Radiation Expos...		18 Years -	UNC Lineberger Comprehensive Cancer Center

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