Trial Outcomes & Findings for Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases (NCT NCT01414738)

Results Overview

The HVLT-R is a validated test to assess neurocognitive function and it incorporates 6 different forms, each including 12 nouns (targets) with 4 words drawn from 3 semantic categories. \*Delayed\*recall was measured by recalling the 12 targets after a 20-minute delay. 1 point is awarded for each successfully recalled target. There is no range- recalling more is more memory. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

50 participants

Primary outcome timeframe

Baseline, 3 months

Results posted on

2021-01-26

Participant Flow

Participant milestones

Participant milestones
Measure	Radiation Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Overall Study STARTED	49
Overall Study Follow-up (3 Months)	18
Overall Study Follow-up (6 Months)	8
Overall Study Follow-up (9 Months)	5
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	44

Reasons for withdrawal

Reasons for withdrawal
Measure	Radiation Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Overall Study Death	26
Overall Study Refused testing	5
Overall Study Lost to Follow-up	2
Overall Study Refused, disease progression	8
Overall Study (Unknown) NOS (Not Otherwise Specified)	3

Baseline Characteristics

Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Age, Continuous	60 years n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants
Race/Ethnicity, Customized White	31 Participants n=5 Participants
Race/Ethnicity, Customized African American	11 Participants n=5 Participants
Race/Ethnicity, Customized Other	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

The HVLT-R is a validated test to assess neurocognitive function and it incorporates 6 different forms, each including 12 nouns (targets) with 4 words drawn from 3 semantic categories. \*Delayed\*recall was measured by recalling the 12 targets after a 20-minute delay. 1 point is awarded for each successfully recalled target. There is no range- recalling more is more memory. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Delayed Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R DR) Score	-10.6 percentage difference Standard Deviation 50.4

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

The HVLT-R is a validated test to assess neurocognitive function and it incorporates 6 different forms, each including 12 nouns (targets) with 4 words drawn from 3 semantic categories. \*Immediate\* recall was measured by memorizing a list of 12 targets for 3 consecutive trials. 1 point is awarded for each successfully recalled target. There is no range- recalling more is more memory. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Immediate Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R)	39.6 percentage difference Standard Deviation 129.4

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

The HVLT-R is a validated test to assess neurocognitive function and it incorporates 6 different forms, each including 12 nouns (targets) with 4 words drawn from 3 semantic categories. \*Delayed recognition\* was measured by using recognition discrimination index. 1 point is awarded for each successfully recalled target. There is no range- recalling more is more memory. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Delayed Recognition Score by Hopkins Verbal Learning Test-Revised (HVLT-R)	-0.4 percentage difference Standard Deviation 19.9

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

Controlled Word Association Test (COWAT) is used to assess language and executive/frontal skills. The patient produces as many words as possible in 1 min. (each) for a specific letter (C, F, L or P, R, W). Requires about 5 min to complete. 1 point is awarded for each word produced. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Neurocognitive Function as Measured by Controlled Word Association Test	3.7 percentage difference Standard Deviation 40.0

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 2 participants who missed the test were excluded from the analysis.

Trail Making Test (TMT) is a measure of visuospatial scanning, attention, sequencing, and speed and executive function. Patients must "connect the dots" either in a numbered sequence or alternating letters and numbers. The TMT has two parts that are referred to as the Trail Making Test Part A and the Trail Making Test Part B. In Part A, the circles are numbered 1 - 25, and the patient should draw lines to connect the numbers in ascending order. Possible score ranges from 0-3 minutes with higher score (more seconds/minutes) indicating significant cognitive impairment. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=16 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Trail Making Test (TMT- A) Score	17.7 percentage difference Standard Deviation 86.6

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 4 participants who missed the test were excluded from the analysis.

Trail Making Test (TMT) is a measure of visuospatial scanning, attention, sequencing, and speed and executive function. Patients must "connect the dots" either in a numbered sequence or alternating letters and numbers. The TMT has two parts that are referred to as the Trail Making Test Part A and the Trail Making Test Part B. In Part B, the circles include both numbers (1 - 13) and letters (A - L). Possible score ranges from 0-5 minutes with higher score (more seconds/minutes) indicating significant cognitive impairment.

Outcome measures

Outcome measures
Measure	Radiation n=14 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Trail Making Test (TMT- B) Score	12.0 percentage difference Standard Deviation 34.9

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

Medical Outcomes Scale (MOS) assess cognitive function with possible score range from 0-100, with higher scores indicating better outcome. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Cognitive Function as Measured by Medical Outcomes Scale (MOS)	3.2 percentage difference Standard Deviation 18.2

SECONDARY outcome

Timeframe: Baseline, at 3 months

Population: Complete case analysis was done for this and 1 participant who missed the test was excluded from the analysis.

Mini-Mental Status Examination (MMSE) is a brief, standardized tool to grade patients' global cognitive function. Possible scores range from 0-30, with lower score indicating severe cognitive impairment. Mean change was calculated by the following formula: 100\*(3 month - baseline) / baseline

Outcome measures

Outcome measures
Measure	Radiation n=17 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Cognitive Function as Measured by Mini-Mental Status Examination (MMSE)	-0.1 percentage difference Standard Deviation 7.0

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Complete case analysis was done for this and 2 participants who missed the test were excluded from the analysis.

The MFI-20 is a multidimensional, self-reporting instrument designed to measure fatigue. It covers the following dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. Possible subscore ranges from 4 to 20 is reported for each dimension, with 20 corresponding to maximal fatigue.

Outcome measures

Outcome measures
Measure	Radiation n=16 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Mean Change in Relative Fatigue as Measured by Multidimensional Fatigue Inventory (MFI-20) Scores	6.6 percentage difference Standard Deviation 32.2

SECONDARY outcome

Timeframe: 1 year

Cumulative incidence of local failure, defined as tumor recurrence . Percent local failure at 1 year. The Cox proportional hazards regression model will be used to evaluate Cumulative incidence of local failure. This is to evaluate local control of brain metastases treated with integrated boost.

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Cumulative Incidence of Local Failure	8.8 hazard (probability) of tumor recurrence Interval 2.7 to 19.6

SECONDARY outcome

Timeframe: 1 year

Cumulative incidence of intracranial failure was estimated by the Cox proportional hazards regression model. Intracranial failure is any failure in the brain.

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Cumulative Incidence of Intracranial Failure	21.3 hazard (probability) of tumor recurrence Interval 10.7 to 34.2

SECONDARY outcome

Timeframe: 1 year

Percentage of participants with local failures within the region of brain within the CTV (Clinical Target Volume ) receiving 20 Gy

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Percentage of Participants With Local Failures Within the Region of Brain Within the CTV Receiving 20 Gy	10.5 percentage of participants

SECONDARY outcome

Timeframe: 5 months

Recurrence in the hippocampus was noted after hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT)

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Number of Participants With Recurrence in the Hippocampus	1 Participants

SECONDARY outcome

Timeframe: 39 months

Tumor progression is measured radiographically. The Kaplan-Meier estimator was used to determine the median time to death for this patient population.

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Median Progression Free Survival	2.9 months Interval 1.5 to 4.0

SECONDARY outcome

Timeframe: 39 months

Overall survival is measured by the Kaplan-Meier estimator used to determine the median overall survival for this patient population.

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Median Overall Survival.	9 months Interval 4.07 to 14.87

SECONDARY outcome

Timeframe: From start of treatment up to 39 months

The adverse event (AE) including any adverse event would be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome measures

Outcome measures
Measure	Radiation n=49 Participants Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Number of Adverse Events Grade 3 or Higher Based on CTCAE (Common Terminology Criteria for Adverse Events) Criteria.	3 events

SECONDARY outcome

Timeframe: 39 months

Population: This data was not collected as we were no longer interested in collecting this.

Quality of life will be assessed using the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR). The FACT-BR is a multidimensional, self-report quality of life instrument specifically designed and validated for use with brain malignancy patients. It is written at the 4th grade reading level and can be completed in 5-10 minutes with little or no assistance in patients who are not neurologically incapacitated. It measures quality of life related to symptoms or problems across 5 scales: physical well-being (7 items); social/family well-being (7 items);emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Items are rated on a 5-point scale (0-5): 0-"not at all", 1- "a little bit", 2-"somewhat", 3-"quite a bit" and 4-"very much", with HIGHER scores indicating a better quality of life.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 39 months

Population: This data was not collected as we were no longer interested in collecting this.

The EQ (Euroqol)-5D (5 Dimension) health related quality of life questionnaire is a standardized instrument for use as a measure of health outcome. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status. . The US version of the EQ-5D will be used, to enable mapping of general HR-QoL (Health-related quality of life) scores from EQ-5D scores into health state utility scores (ranging from 0 to 1) for the US population. Possible scores range from 0 to 1, with HIGHER scores indicating a better quality of life.

Outcome measures

Outcome data not reported

Adverse Events

Radiation

Serious events: 0 serious events

Other events: 13 other events

Deaths: 26 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Radiation n=49 participants at risk Whole-Brain Radiotherapy Radiotherapy: Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Skin and subcutaneous tissue disorders Alopecia	8.2% 4/49 • 39 months
Nervous system disorders Fatigue	26.5% 13/49 • 39 months
Metabolism and nutrition disorders Anorexia	4.1% 2/49 • 39 months
General disorders Aphasia	2.0% 1/49 • 39 months
Gastrointestinal disorders Constipation	2.0% 1/49 • 39 months
General disorders Dizziness	4.1% 2/49 • 39 months
Nervous system disorders Dysarthria	2.0% 1/49 • 39 months
Blood and lymphatic system disorders Edema face	2.0% 1/49 • 39 months
Nervous system disorders Gait disturbance	2.0% 1/49 • 39 months
General disorders Headache	20.4% 10/49 • 39 months
Ear and labyrinth disorders Hearing loss	2.0% 1/49 • 39 months
General disorders Insomnia	2.0% 1/49 • 39 months
General disorders Nausea	20.4% 10/49 • 39 months
Nervous system disorders Seizures	2.0% 1/49 • 39 months
Gastrointestinal disorders Vomiting	4.1% 2/49 • 39 months

Additional Information

Dr. Robert Timmerman

UT Southwestern Medical Center

Phone: 214/645-7637

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place