Back to resultsHippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases
Primary Purpose
Brain Neoplasms, Adult, Malignant
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Radiotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Brain Neoplasms, Adult, Malignant
Eligibility Criteria
Inclusion Criteria:
- Pathologically (histologically or cytologically) proven diagnosis of a non-hematopoietic malignancy other than small cell lung cancer and germ cell malignancy.. Direct biopsy of CNS (central nervous system) lesions is not necessarily required although could constitute an allowed site of tissue confirmation as medically prudent. Patients who have been disease free for more than 5 years prior to the appearance of CNS metastases should undergo repeat biopsy of either a systemic metastasis or the CNS metastases to confirm the recurrent malignancy.
- Patients with measurable brain metastasis outside a 5-mm margin around either hippocampus
- Patients with measurable brain metastasis who have not been or will not be treated with SRS (stereotactic radiosurgery ) or surgical resection (Note: These treatment options are only permitted at relapse)
- History/physical examination within 28 days prior to registration
- Patients must fall into RTOG (Radiation Therapy Oncology Group) recursive partitioning analysis (RPA) class I or II
- Patients must have a life expectancy of at least 4 months.
- Age ≥ 18 years
- Karnofsky performance status ≥ 70
- Patients must provide study-specific informed consent prior to study entry
- Women of childbearing potential and male participants must practice adequate contraception
- Women of childbearing potential must have a negative, qualitative serum pregnancy test ≤2 weeks prior to study entry
Exclusion Criteria:
- Patients with greater than 9 discrete metastases on MRI.
- Patients with leptomeningeal metastases
- Patients with measurable brain metastasis not resulting from small cell lung cancer and germ cell malignancy
- Plan for chemotherapy or targeted therapies during WBRT or over the subsequent 7 days
- Contraindication to MR (Magnetic resonance) imaging such as implanted metal devices or foreign bodies, severe claustrophobia AND patients unable to receive gadolinium contrast agents
- Serum creatinine > 1.4 mg/dl ≤ 28 days prior to study entry
- Prior radiation therapy to the brain
- Patients planning to undergo radiosurgery to any CNS lesion OR patients planning to have surgical resection of ALL of their CNS lesions
Sites / Locations
- University of Texas Southwestern Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Radiation
Arm Description
Whole-Brain Radiotherapy
Outcomes
Primary Outcome Measures
Mean Change in *Delayed* Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R DR) Score
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
Secondary Outcome Measures
Mean Change in *Immediate* Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R)
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
Mean Change in *Delayed Recognition* Score by Hopkins Verbal Learning Test-Revised (HVLT-R)
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
Mean Change in Neurocognitive Function as Measured by Controlled Word Association Test
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
Mean Change in Trail Making Test (TMT- A) Score
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
Mean Change in Trail Making Test (TMT- B) Score
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.
Mean Change in Cognitive Function as Measured by Medical Outcomes Scale (MOS)
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
Mean Change in Cognitive Function as Measured by Mini-Mental Status Examination (MMSE)
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
Mean Change in Relative Fatigue as Measured by Multidimensional Fatigue Inventory (MFI-20) Scores
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.
Cumulative Incidence of Local Failure
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.
Cumulative Incidence of Intracranial Failure
Cumulative incidence of intracranial failure was estimated by the Cox proportional hazards regression model.
Intracranial failure is any failure in the brain.
Percentage of Participants With Local Failures Within the Region of Brain Within the CTV Receiving 20 Gy
Percentage of participants with local failures within the region of brain within the CTV (Clinical Target Volume ) receiving 20 Gy
Number of Participants With Recurrence in the Hippocampus
Recurrence in the hippocampus was noted after hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT)
Median Progression Free Survival
Tumor progression is measured radiographically. The Kaplan-Meier estimator was used to determine the median time to death for this patient population.
Median Overall Survival.
Overall survival is measured by the Kaplan-Meier estimator used to determine the median overall survival for this patient population.
Number of Adverse Events Grade 3 or Higher Based on CTCAE (Common Terminology Criteria for Adverse Events) Criteria.
The adverse event (AE) including any adverse event would be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Health-related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy With Brain Subscale (FACT-BR)
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.
Health-related Quality of Life as Assessed by Euroqol EQ-5D
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.
Full Information
NCT ID
NCT01414738
First Posted
August 10, 2011
Last Updated
January 5, 2021
Sponsor
University of Texas Southwestern Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT01414738
Brief Title
Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases
Official Title
Phase II Trial of Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
October 18, 2011 (Actual)
Primary Completion Date
December 16, 2019 (Actual)
Study Completion Date
December 16, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Texas Southwestern Medical Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The investigators hypothesize that avoidance of the hippocampal region with WBRT (Whole-Brain Radiotherapy ) may delay or reduce the onset, frequency, and/or severity of NCF (neurocognitive function) decline, as measured with clinical neurocognitive tools.
Detailed Description
We propose to use conformal avoidance of the hippocampal region during whole brain radiotherapy to reduce the dose to the hippocampi, thereby putatively limiting the radiation-induced inflammation of the hippocampal region and subsequent alteration of the microenvironment of the neural progenitor cells
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Neoplasms, Adult, Malignant
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Radiation
Arm Type
Experimental
Arm Description
Whole-Brain Radiotherapy
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Description
Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous Integrated Boost
Primary Outcome Measure Information:
Title
Mean Change in *Delayed* Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R DR) Score
Description
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
Time Frame
Baseline, 3 months
Secondary Outcome Measure Information:
Title
Mean Change in *Immediate* Recall Score by Hopkins Verbal Learning Test-Revised (HVLT-R)
Description
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
Time Frame
Baseline, at 3 months
Title
Mean Change in *Delayed Recognition* Score by Hopkins Verbal Learning Test-Revised (HVLT-R)
Description
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
Time Frame
Baseline, 3 months
Title
Mean Change in Neurocognitive Function as Measured by Controlled Word Association Test
Description
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
Time Frame
Baseline, at 3 months
Title
Mean Change in Trail Making Test (TMT- A) Score
Description
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
Time Frame
Baseline, at 3 months
Title
Mean Change in Trail Making Test (TMT- B) Score
Description
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.
Time Frame
Baseline, at 3 months
Title
Mean Change in Cognitive Function as Measured by Medical Outcomes Scale (MOS)
Description
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
Time Frame
Baseline, at 3 months
Title
Mean Change in Cognitive Function as Measured by Mini-Mental Status Examination (MMSE)
Description
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
Time Frame
Baseline, at 3 months
Title
Mean Change in Relative Fatigue as Measured by Multidimensional Fatigue Inventory (MFI-20) Scores
Description
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.
Time Frame
Baseline, 3 months
Title
Cumulative Incidence of Local Failure
Description
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.
Time Frame
1 year
Title
Cumulative Incidence of Intracranial Failure
Description
Cumulative incidence of intracranial failure was estimated by the Cox proportional hazards regression model.
Intracranial failure is any failure in the brain.
Time Frame
1 year
Title
Percentage of Participants With Local Failures Within the Region of Brain Within the CTV Receiving 20 Gy
Description
Percentage of participants with local failures within the region of brain within the CTV (Clinical Target Volume ) receiving 20 Gy
Time Frame
1 year
Title
Number of Participants With Recurrence in the Hippocampus
Description
Recurrence in the hippocampus was noted after hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT)
Time Frame
5 months
Title
Median Progression Free Survival
Description
Tumor progression is measured radiographically. The Kaplan-Meier estimator was used to determine the median time to death for this patient population.
Time Frame
39 months
Title
Median Overall Survival.
Description
Overall survival is measured by the Kaplan-Meier estimator used to determine the median overall survival for this patient population.
Time Frame
39 months
Title
Number of Adverse Events Grade 3 or Higher Based on CTCAE (Common Terminology Criteria for Adverse Events) Criteria.
Description
The adverse event (AE) including any adverse event would be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame
From start of treatment up to 39 months
Title
Health-related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy With Brain Subscale (FACT-BR)
Description
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.
Time Frame
39 months
Title
Health-related Quality of Life as Assessed by Euroqol EQ-5D
Description
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.
Time Frame
39 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Pathologically (histologically or cytologically) proven diagnosis of a non-hematopoietic malignancy other than small cell lung cancer and germ cell malignancy.. Direct biopsy of CNS (central nervous system) lesions is not necessarily required although could constitute an allowed site of tissue confirmation as medically prudent. Patients who have been disease free for more than 5 years prior to the appearance of CNS metastases should undergo repeat biopsy of either a systemic metastasis or the CNS metastases to confirm the recurrent malignancy.
Patients with measurable brain metastasis outside a 5-mm margin around either hippocampus
Patients with measurable brain metastasis who have not been or will not be treated with SRS (stereotactic radiosurgery ) or surgical resection (Note: These treatment options are only permitted at relapse)
History/physical examination within 28 days prior to registration
Patients must fall into RTOG (Radiation Therapy Oncology Group) recursive partitioning analysis (RPA) class I or II
Patients must have a life expectancy of at least 4 months.
Age ≥ 18 years
Karnofsky performance status ≥ 70
Patients must provide study-specific informed consent prior to study entry
Women of childbearing potential and male participants must practice adequate contraception
Women of childbearing potential must have a negative, qualitative serum pregnancy test ≤2 weeks prior to study entry
Exclusion Criteria:
Patients with greater than 9 discrete metastases on MRI.
Patients with leptomeningeal metastases
Patients with measurable brain metastasis not resulting from small cell lung cancer and germ cell malignancy
Plan for chemotherapy or targeted therapies during WBRT or over the subsequent 7 days
Contraindication to MR (Magnetic resonance) imaging such as implanted metal devices or foreign bodies, severe claustrophobia AND patients unable to receive gadolinium contrast agents
Serum creatinine > 1.4 mg/dl ≤ 28 days prior to study entry
Prior radiation therapy to the brain
Patients planning to undergo radiosurgery to any CNS lesion OR patients planning to have surgical resection of ALL of their CNS lesions
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Timmerman, MD
Organizational Affiliation
UT Southwestern Medical Center Dallas
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases
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