Trial Outcomes & Findings for Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Limited Stage or Extensive Stage Small Cell Lung Cancer (NCT NCT02635009)

Last Updated: 2024-07-17

Results Overview

The HVLT-R delayed recall test assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials to recall after a 20-minute delay. The score is the sum of the number of words correctly recalled and ranges from 0 to 36, with a higher score indicating better functioning. Deterioration is defined a decrease from baseline of at least 3 points.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2/PHASE3

Target enrollment

418 participants

Primary outcome timeframe

Baseline and six months

Results posted on

2024-07-17

Participant Flow

Patients were screened in order to determine whether their neurocognitive functioning was healthy enough to participate. This was defined as a score of 2 or higher on the Delayed Recall subscale of the Hopkins Verbal Learning Test (HVLT). HVLT testing was done after initial enrollment, but prior to randomization. Of 418 participants screened, 393 were randomized.

Participant milestones

Participant milestones
Measure	PCI Using 3DCRT Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Overall Study STARTED	196	197
Overall Study Phase II Analysis	89	87
Overall Study Adverse Event Population	191	189
Overall Study COMPLETED	196	197
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Limited Stage or Extensive Stage Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PCI Using 3DCRT n=196 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT n=197 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.	Total n=393 Participants Total of all reporting groups
Age, Continuous	64 years n=5 Participants	65 years n=7 Participants	64 years n=5 Participants
Age, Customized Age (years) · ≤ 49	12 Participants n=5 Participants	8 Participants n=7 Participants	20 Participants n=5 Participants
Age, Customized Age (years) · 50-59	49 Participants n=5 Participants	37 Participants n=7 Participants	86 Participants n=5 Participants
Age, Customized Age (years) · 60-69	75 Participants n=5 Participants	102 Participants n=7 Participants	177 Participants n=5 Participants
Age, Customized Age (years) · ≥ 70	60 Participants n=5 Participants	50 Participants n=7 Participants	110 Participants n=5 Participants
Sex: Female, Male Female	127 Participants n=5 Participants	114 Participants n=7 Participants	241 Participants n=5 Participants
Sex: Female, Male Male	69 Participants n=5 Participants	83 Participants n=7 Participants	152 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	185 Participants n=5 Participants	190 Participants n=7 Participants	375 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	15 Participants n=5 Participants	10 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) White	175 Participants n=5 Participants	180 Participants n=7 Participants	355 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Zubrod performance status 0	79 Participants n=5 Participants	83 Participants n=7 Participants	162 Participants n=5 Participants
Zubrod performance status 1	100 Participants n=5 Participants	105 Participants n=7 Participants	205 Participants n=5 Participants
Zubrod performance status 2	17 Participants n=5 Participants	9 Participants n=7 Participants	26 Participants n=5 Participants
Planned concurrent memantine use No	96 Participants n=5 Participants	102 Participants n=7 Participants	198 Participants n=5 Participants
Planned concurrent memantine use Yes	100 Participants n=5 Participants	95 Participants n=7 Participants	195 Participants n=5 Participants
Extent of disease Limited stage disease (LD)	142 Participants n=5 Participants	133 Participants n=7 Participants	275 Participants n=5 Participants
Extent of disease Extensive stage disease (ED)	54 Participants n=5 Participants	64 Participants n=7 Participants	118 Participants n=5 Participants
Education level Grade school	9 Participants n=5 Participants	2 Participants n=7 Participants	11 Participants n=5 Participants
Education level More than grade school and did not graduate high school	30 Participants n=5 Participants	17 Participants n=7 Participants	47 Participants n=5 Participants
Education level High school graduate or GED	73 Participants n=5 Participants	79 Participants n=7 Participants	152 Participants n=5 Participants
Education level Some college or associate's degree	46 Participants n=5 Participants	64 Participants n=7 Participants	110 Participants n=5 Participants
Education level Bachelor's degree	23 Participants n=5 Participants	23 Participants n=7 Participants	46 Participants n=5 Participants
Education level Advanced degree	14 Participants n=5 Participants	9 Participants n=7 Participants	23 Participants n=5 Participants
Education level Unknown	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Smoking status (self-reported) Never smoked	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Smoking status (self-reported) Former smoker	62 Participants n=5 Participants	61 Participants n=7 Participants	123 Participants n=5 Participants
Smoking status (self-reported) Current smoker	106 Participants n=5 Participants	110 Participants n=7 Participants	216 Participants n=5 Participants
Smoking status (self-reported) Unknown	23 Participants n=5 Participants	21 Participants n=7 Participants	44 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and six months

Population: Randomized patients with score at baseline and 6 months

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=110 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=106 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in HVLT-R Delayed Recall Score at Six Months (Phase III)	33 Participants	27 Participants

PRIMARY outcome

Timeframe: From baseline to 12 months

Population: Phase II randomized participants on study for at least one year.

Intracranial relapse, defined as the development of a new brain metastasis as documented on brain MRI with contrast or head CT with contrast.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=86 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=85 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Intracranial Relapse at 12 Months (Phase II)	16 Participants	12 Participants

SECONDARY outcome

Timeframe: Randomization to date of failure, death, or last known follow-up whichever occurred first. Maximum follow-up at time of analysis was 7.2 years.

Population: Randomized participants

Neurocognitive failure is defined as the first instance of neurocognitive decline in any of six assessments, as determined my reliable change index: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) part A, TMT part B, and Controlled Oral Word Association (COWA). Failure time is defined as time from randomization to failure, death (competing event), or last follow-up (censored). Neurocognitive failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared, which is reported in the statistical analysis results. Six-month rates are reported here. Analysis occurred after all patients had been on study for at least six months.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=196 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=197 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Percentage of Participants With Neurocognitive Failure (Phase III)	57.0 percentage of participants Interval 49.6 to 63.8	52.7 percentage of participants Interval 45.3 to 59.5

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=146 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=145 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III) 3 months	47 Participants	47 Participants
Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III) 6 months	33 Participants	35 Participants
Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III) 12 months	20 Participants	17 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

he HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 12 months.

Population: Randomized patients with HVLT-R Delayed Recall score at baseline and: 3 or 12 months.

The HVLT-R Delayed Recall test assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials, this test requires recalling the 12 targets after a 20-minute delay. Raw scores are sum of the number of targets correctly recalled. The score ranges from 0 to 12. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 3 points. Six-month results are reported as the primary endpoint.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=146 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=145 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III) 3 months	40 Participants	34 Participants
Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III) 12 months	23 Participants	19 Participants

SECONDARY outcome

Timeframe: Baseline, 18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and: 3, 6, or 12 months.

The HVLT-R Delayed Recognition assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials and recalling the 12 targets after a 20-minute delay, the test involves then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are the sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified. The score ranges from -12 to 12 for recognition. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 2 points.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=146 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=145 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III) 3 months	49 Participants	45 Participants
Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III) 6 months	11 Participants	11 Participants
Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III) 12 months	19 Participants	22 Participants

SECONDARY outcome

Timeframe: Baseline, 18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with TMT Part A at baseline and 3, 6, or 12 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A, reported here), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order. The score is the amount of time, in seconds, that it takes the patient to complete the maze. The range for Part A is 0 to 180 (3 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 12 seconds.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=144 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=144 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III) 12 months	22 Participants	14 Participants
Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III) 3 months	27 Participants	30 Participants
Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III) 6 months	21 Participants	26 Participants

SECONDARY outcome

Timeframe: Baseline, 18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the second part (Part B, reported here), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete the maze. The score range for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 26 seconds.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=142 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=143 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in TMT Part B Score (Phase III) 12 months	22 Participants	19 Participants
Number of Participants With Deterioration in TMT Part B Score (Phase III) 3 months	43 Participants	38 Participants
Number of Participants With Deterioration in TMT Part B Score (Phase III) 6 months	26 Participants	38 Participants

SECONDARY outcome

Timeframe: Baseline, 18, 24 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the second part (Part B, reported here), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete the maze. The score range for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 26 seconds. If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Deterioration is defined an increase from baseline of at least 12 words.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=145 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=145 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in Controlled Oral Word Association (COWA) Score (Phase III) 3 months	13 Participants	24 Participants
Number of Participants With Deterioration in Controlled Oral Word Association (COWA) Score (Phase III) 6 months	3 Participants	12 Participants
Number of Participants With Deterioration in Controlled Oral Word Association (COWA) Score (Phase III) 12 months	7 Participants	14 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of treatment to last known follow-up . Maximum follow-up time was 7.2 years.

Population: Randomized participants who received radiation therapy.

Common Terminology Criteria for Adverse Events (version 5) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=191 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=189 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants by Highest Grade Adverse Event Reported (Phase III) Grade 3	47 Participants	47 Participants
Number of Participants by Highest Grade Adverse Event Reported (Phase III) Grade 1	27 Participants	30 Participants
Number of Participants by Highest Grade Adverse Event Reported (Phase III) Grade 2	78 Participants	75 Participants
Number of Participants by Highest Grade Adverse Event Reported (Phase III) Grade 4	12 Participants	8 Participants
Number of Participants by Highest Grade Adverse Event Reported (Phase III) Grade 5	1 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. Global Health Status is considered a measure of overall quality of life and is calculated from two questions whose raw scores are averaged and then transformed to a range of 0 (worst) to 100 (best). Deterioration is defined a reduction of 10% from baseline.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=146 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) Global Health Status (Phase III) 6 months	39 Participants	43 Participants
Number of Participants With Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) Global Health Status (Phase III) 3 months	57 Participants	67 Participants
Number of Participants With Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) Global Health Status (Phase III) 12 months	22 Participants	26 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=147 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-C30 Physical Functioning Score (Phase III) 3 months	39 Participants	60 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Physical Functioning Score (Phase III) 6 months	30 Participants	46 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Physical Functioning Score (Phase III) 12 months	25 Participants	28 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=147 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-C30 Role Functioning Score (Phase III) 3 months	54 Participants	56 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Role Functioning Score (Phase III) 6 months	30 Participants	41 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Role Functioning Score (Phase III) 12 months	20 Participants	24 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=147 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-C30 Emotional Functioning Score (Phase III) 3 months	46 Participants	41 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Emotional Functioning Score (Phase III) 6 months	31 Participants	33 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Emotional Functioning Score (Phase III) 12 months	19 Participants	19 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=147 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-C30 Social Functioning Score (Phase III) 6 months	21 Participants	30 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Social Functioning Score (Phase III) 12 months	17 Participants	13 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Social Functioning Score (Phase III) 3 months	39 Participants	46 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=147 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=137 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-C30 Cognitive Functioning Score (Phase III) 3 months	58 Participants	45 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Cognitive Functioning Score (Phase III) 12 months	37 Participants	30 Participants
Number of Participants With Deterioration in EORTC QLQ-C30 Cognitive Functioning Score (Phase III) 6 months	41 Participants	55 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The EORTC QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=149 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=140 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC Quality of Life Questionnaire BN-20 (QLQ-BN20) Motor Dysfunction Score (Phase III) 3 months	57 Participants	60 Participants
Number of Participants With Deterioration in EORTC Quality of Life Questionnaire BN-20 (QLQ-BN20) Motor Dysfunction Score (Phase III) 6 months	49 Participants	51 Participants
Number of Participants With Deterioration in EORTC Quality of Life Questionnaire BN-20 (QLQ-BN20) Motor Dysfunction Score (Phase III) 12 months	37 Participants	41 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 3, 6, 12 months.

Population: Randomized patients with score at baseline and 3, 6, or 12 months.

The QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=149 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=140 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Number of Participants With Deterioration in EORTC QLQ-BN20 Communication Deficit Score (Phase III) 6 months	45 Participants	42 Participants
Number of Participants With Deterioration in EORTC QLQ-BN20 Communication Deficit Score (Phase III) 12 months	31 Participants	28 Participants
Number of Participants With Deterioration in EORTC QLQ-BN20 Communication Deficit Score (Phase III) 3 months	50 Participants	40 Participants

SECONDARY outcome

Timeframe: Baseline,18, 24 months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 6 months

Population: Randomized participants with values at 6 months. The protocol specifies that the treatment arms are combined into a single group for this outcome measure.

The Pearson correlation coefficient was calculated for EORTC QLQ-C30 (physical, role, emotional, cognitive, and social functioning domains and global health status) and QLQ-BN20 (motor dysfunction and communication deficit) versus the standardized neurocognitive function (HVLT-R total recall, HVLT-R delayed recall, HVLT-R delayed recognition, COWA, TMT parts A and B) and the Clinical Trial Battery Composite (CTB Comp) score (mean of the z-scores for the six NCF scores) for all patients, treatment arms combined. The Pearson correlation coefficient is computed for each pair of measurements, resulting in 48 correlation coefficients. Possible values range from -1 (negatively correlated) to 1(positively correlated), with 0 indicating no correlation. A correlation with a value in range -0.35 to 0.35 is considered weak and is indicated by "0" in the table. Because of the large number of comparisons, only individual correlation coefficients outside that range are listed here.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=212 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Correlation of Quality of Life and Neurocognitive Function (NCF) Measures at 6 Months EORTC QLQ-C30 Physical functioning vs. NCF CTB Comp Score	0.3619 correlation coefficient	—
Correlation of Quality of Life and Neurocognitive Function (NCF) Measures at 6 Months All others	0 correlation coefficient	—

SECONDARY outcome

Timeframe: Baseline to two years

The incremental cost per quality-adjusted life year (QALY) ratio will be calculated as total cost of the PCI with HA using IMRT arm (Arm 2) minus total cost of the PCI using 3DCRT arm (Arm 1), divided by the quality adjusted survival of the Arm 1 patients minus the quality adjusted survival of Arm 2 patients.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the date of randomization to the date of death or last follow-up. Maximum follow-up time at time of analysis was 7.2 years.

Population: Randomized participants

Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all patients had been on study for at least 8 months.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=196 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=197 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Overall Survival (Phase III)	24.9 months Interval 17.8 to 36.4	20.7 months Interval 17.0 to 34.7

SECONDARY outcome

Timeframe: From date of randomization to date of intracranial relapse, death, or last known follow-up, whichever occurred first. Maximum follow-up at time of analysis was 7.2 years.

Population: Randomized participants

Intracranial relapse is defined as the development of a new brain metastasis as documented on brain MRI with contrast or head CT with contrast. Time to intracranial relapse is defined as time from randomization to the date of first intracranial relapse, last known follow-up (censored), or death without intracranial relapse (competing risk), whichever occurred first. Intracranial relapse rates are estimated using the cumulative incidence method. The distributions of intracranial relapse times are compared between the arms, which is reported in the statistical analysis results. One-year rates are provided here. Analysis occurred at time of the phase III primary analysis.

Outcome measures

Outcome measures
Measure	PCI Using 3DCRT (Arm 1) n=196 Participants Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.	PCI With HA Using IMRT (Arm 1) n=197 Participants PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.
Intracranial Relapse Rate (Phase III)	15.9 percentage of participants Interval 11.0 to 21.6	15.7 percentage of participants Interval 10.9 to 21.4

SECONDARY outcome

Timeframe: Baseline to 6 months

Pearson correlation coefficients will be used to assess the effect of hippocampal volume and FLAIR volume change on baseline neurocognitive function, as measured by the HVLT-R, COWA, and TMT, separately for each arm.

Outcome measures

Outcome data not reported

Adverse Events

PCI Using 3DCRT

Serious events: 26 serious events

Other events: 154 other events

Deaths: 118 deaths

PCI With HA Using IMRT

Serious events: 17 serious events

Other events: 152 other events

Deaths: 112 deaths

Serious adverse events

Other adverse events

Additional Information

Wendy Seiferheld

NRG Oncology

Phone: 2155743208

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER