A Phase 2 interventional study of intensity-modulated radiation therapy in Cognitive/Functional Effects, Metastatic Cancer and Unspecified Adult Solid Tumor, Protocol Specific, sponsored by Radiation Therapy Oncology Group. Completed at 63 sites in 2 countries. Open to participants aged 18 Years to 120 Years. Per ClinicalTrials.gov, last updated 2017-09-27.
Sponsored by Radiation Therapy Oncology Group · Phase 2, Interventional, and Treatment
RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells.
PURPOSE: This phase II trial is studying how well avoiding the hippocampus during whole-brain radiation therapy works in treating patients with brain metastases.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study.
Patients undergo 10 fractions of intensity-modulated whole-brain radiotherapy (WBRT), avoiding hippocampal (HA) regions, once daily, 5 days a week, for 2-2½ weeks.
Patients neurocognitive functions (delayed recall, auditory and visual learning, and memory) are evaluated by the Hopkins Verbal Learning Test-Revised (HVTL-R), The One Card Learning Test (OCLT), and the International Shopping List Test (ISLT) at baseline and periodically during study.
Patients may undergo serum, plasma, or whole blood collection at baseline and at 4 months after completion of HA-WBRT for correlative studies.
Patients may complete the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR), and the Barthel Index of Activities of Daily Living (ADLs) quality-of-life questionnaires at baseline and periodically during study and follow up.
After completion of study therapy, patients are followed up periodically.
1,960 studies on the registry are indexed under Brain Neoplasms; 515 are open to participants now.
This study's enrollment of 113 is above the median of 40 across 1,458 interventional studies indexed under Brain Neoplasms.
Browse Brain Neoplasms studies →Radiation Therapy Oncology Group is the lead sponsor of 154 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Histologically or cytologically confirmed non-hematopoietic malignancy within the past 5 years
Have not been or will not be treated with stereotactic radiosurgery (SRS) or surgical resection
EXCLUSION CRITERIA:
Severe, active co-morbidity including any of the following:
Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Radiation: intensity-modulated radiation therapy
30 Gy in 10 fractions to the whole brain using intensity-modulated radiation therapy excluding the hippocampal avoidance area. Bilateral hippocampal contours manually generated on the fused planning MRI CT image set by the treating physician according to protocol-specified contouring instructions. Hippocampal avoidance regions generated by three-dimensionally expanding the hippocampal contours by 5 mm.
Also known as: IMRT
Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)
Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100\*\[(baseline score - 4 month score)/ baseline score\]
Time frame: Baseline and 4 months from start of treatment
Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT)
The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
Time frame: Baseline and 4 months from start of treatment
Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT)
The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
Time frame: Baseline and 4 months from start of treatment
Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br)
The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires \>= 50% of items to be completed while the overall response rate must be \> 80%. If items are missing, the subscale scores can be prorated.
Time frame: Baseline and 4 months from start of treatment
Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL)
The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.
Time frame: Baseline and 4 months from start of treatment
Overall Survival
Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.
Time frame: Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
Progression-free Survival
Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions \< 1cm, at least 25% for lesions \>=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).
Time frame: Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment
For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
Time frame: From start of treatment to 12 months from start of treatment
ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function
Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure
Time frame: Baseline and 4 months from start of treatment
| Milestone | WBRT With Hippocampal Avoidance |
|---|---|
| Started | 113 |
| Completed | 100 |
| Not completed | 13 |
| Withdrew: Protocol violation | 6 |
| Withdrew: No protocol treatment | 7 |
Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100\*\[(baseline score - 4 month score)/ baseline score\]
| percent change | WBRT With Hippocampal Avoidance |
|---|---|
| Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) | 7.0 (-4.7 to 18.7) |
The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
| percent change | WBRT With Hippocampal Avoidance |
|---|---|
| Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT) | 18.0 (5.5 to 30.5) |
The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
| percent change | WBRT With Hippocampal Avoidance |
|---|---|
| Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT) | -8 (-16.9 to 0.9) |
The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires \>= 50% of items to be completed while the overall response rate must be \> 80%. If items are missing, the subscale scores can be prorated.
| units on a scale | WBRT With Hippocampal Avoidance |
|---|---|
| Baseline | 121.25 (74 to 158) |
| 2 month | 111.94 (85 to 158) |
| 4 month | 115 (81 to 159) |
| 6 month | 126.22 (90.83 to 159) |
The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.
| units on a scale | WBRT With Hippocampal Avoidance |
|---|---|
| Baseline | 20 (10 to 21) |
| 2 month | 20 (5 to 20) |
| 4 month | 20 (7 to 20) |
| 6 month | 20 (13 to 20) |
Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.
| months | WBRT With Hippocampal Avoidance |
|---|---|
| Overall Survival | 6.8 (4.8 to 10.9) |
Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions \< 1cm, at least 25% for lesions \>=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).
| months | WBRT With Hippocampal Avoidance |
|---|---|
| Progression-free Survival | 5.9 (4.7 to 8.4) |
For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
| Participants | WBRT With Hippocampal Avoidance |
|---|---|
| The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment | 2 |
Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure
No measurements were reported for this outcome.
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| WBRT With Hippocampal Avoidance | — | 13/96 (13.5%) | 46/96 (47.9%) |
| Event | WBRT With Hippocampal Avoidance |
|---|---|
| Colonic perforationGastrointestinal disorders | 2/96 |
| Death NOSGeneral disorders | 2/96 |
| DehydrationMetabolism and nutrition disorders | 2/96 |
| Cognitive disturbanceNervous system disorders | 2/96 |
| SeizureNervous system disorders | 2/96 |
| Thromboembolic eventVascular disorders | 2/96 |
| AnemiaBlood and lymphatic system disorders | 1/96 |
| Chest pain - cardiacCardiac disorders | 1/96 |
| Pericardial effusionCardiac disorders | 1/96 |
| Sinus tachycardiaCardiac disorders | 1/96 |
| Event | WBRT With Hippocampal Avoidance |
|---|---|
| FatigueGeneral disorders | 34/96 |
| AlopeciaSkin and subcutaneous tissue disorders | 21/96 |
| HeadacheNervous system disorders | 17/96 |
| NauseaGastrointestinal disorders | 13/96 |
| AnorexiaMetabolism and nutrition disorders | 13/96 |
| Memory impairmentNervous system disorders | 10/96 |
| Blurred visionEye disorders | 8/96 |
| Gait disturbanceGeneral disorders | 7/96 |
| Weight lossInvestigations | 7/96 |
| VomitingGastrointestinal disorders | 6/96 |
Eligible patients
| Age, Continuous(years) | WBRT With Hippocampal Avoidance |
|---|---|
| Median | 61 (28 to 83) |
| Sex: Female, Male(Participants) | WBRT With Hippocampal Avoidance |
|---|---|
| Female | 52 |
| Male | 48 |
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