Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Matthew A Kirkman; Julia Day; Karin Gehring; Karolis Zienius; David Grosshans; Martin Taphoorn; Jing Li; Paul D Brown

doi:10.1002/14651858.CD011335.pub3

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Figure 1

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Cognitive functioning composite score
Brown 2013

Analysis 1.1

Comparison 1: Prevention: Memantine versus placebo, Outcome 1: Cognitive functioning composite score

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5	Heading 6	Heading 7
Cognitive functioning sub‐tests
Short‐term verbal memory
Brown 2013






Long‐term verbal memory (recall)
Brown 2013






Long‐term verbal memory (recognition)
Brown 2013






Trail making test A
Brown 2013






Trail making test B
Brown 2013






Verbal fluency
Brown 2013

Analysis 1.2

Comparison 1: Prevention: Memantine versus placebo, Outcome 2: Cognitive functioning sub‐tests

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Analysis 1.3

Comparison 1: Prevention: Memantine versus placebo, Outcome 3: Adverse events

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
General cognitive functioning
Butler 2007

Analysis 2.1

Comparison 2: Prevention: d‐threo‐methylphenidate versus placebo, Outcome 1: General cognitive functioning

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Depression
Butler 2007

Analysis 2.2

Comparison 2: Prevention: d‐threo‐methylphenidate versus placebo, Outcome 2: Depression

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Analysis 2.3

Comparison 2: Prevention: d‐threo‐methylphenidate versus placebo, Outcome 3: Fatigue

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Quality of life
FACT
Butler 2007
Brain subscale
Butler 2007

Analysis 2.4

Comparison 2: Prevention: d‐threo‐methylphenidate versus placebo, Outcome 4: Quality of life

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Cognitive functioning
Locke 2008

Analysis 3.1

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 1: Cognitive functioning

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Cognitive functioning sub‐test
Attention
Locke 2008
Short‐term verbal memory
Locke 2008
Short‐term visual memory
Locke 2008
Long‐term verbal/visual memory
Locke 2008
Language
Locke 2008

Analysis 3.2

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 2: Cognitive functioning sub‐test

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Mood
Locke 2008

Analysis 3.3

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 3: Mood

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Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Fatigue
Locke 2008

Analysis 3.4

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 4: Fatigue

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Analysis 3.5

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 5: Functional capacity

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Analysis 3.6

Comparison 3: Prevention: Cognitive rehabilitation versus standard care, Outcome 6: Quality of life

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Analysis 4.1

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 1: Cognitive functioning (calculated score)

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Analysis 4.2

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 2: Cognitive functioning (timed tasks)

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Analysis 4.3

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 3: Cognitive functioning (total score)

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Analysis 4.4

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 4: Self‐reported confusion

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Analysis 4.5

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 5: Anxiety

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Analysis 4.6

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 6: Depression

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Analysis 4.7

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 7: Anger

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Analysis 4.8

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 8: Fatigue

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Analysis 4.9

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 9: Sleep

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Analysis 4.10

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 10: Activity

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Analysis 4.11

Comparison 4: Amelioration: Methylphenidate versus modafinil, Outcome 11: Quality of life

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Analysis 5.1

Comparison 5: Amelioration: Donepezil versus placebo, Outcome 1: Cognitive composite score

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Analysis 5.2

Comparison 5: Amelioration: Donepezil versus placebo, Outcome 2: Cognitive functioning (timed tasks)

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Analysis 5.3

Comparison 5: Amelioration: Donepezil versus placebo, Outcome 3: Cognitive functioning (total score)

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Analysis 6.1

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 1: Cognitive performance measures: Goal management training versus wait‐list control

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Analysis 6.2

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 2: Cognitive performance measures: Goal management training versus brain health program

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Analysis 6.3

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 3: Cognitive performance measures: Brain health program versus wait‐list control

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Analysis 6.4

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 4: Patient‐reported outcome measures: Goal management training versus wait‐list control

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Analysis 6.5

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 5: Patient‐reported outcome measures: Goal management training versus brain health program

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Analysis 6.6

Comparison 6: Amelioration: Goal management training versus brain health program versus wait‐listed control, Outcome 6: Patient‐reported outcome measures: Brain health program versus wait‐list control

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Table 1. Summary of findings: Memantine versus placebo

Cognitive functioning measure (standardised scores)	Memantine		Placebo		P
	N	Median change after 24 weeks (IQR)	N	Median change after 24 weeks (IQR)	P
Short‐term verbal memory	77	‐0.23 (‐1.16 to 0.70)	90	‐0.415 (‐1.86 to 0.46)	0.21
Long‐term verbal memory (recall)	76	0 (‐1.67 to 0.59)	90	‐0.90 (‐2.22 to 0.55)	0.06
Long‐term verbal memory (recognition)	76	0 (‐1.12 to 1.43)	90	‐0.72 (‐2.73 to 0.71)	0.01*
Verbal Fluency	78	‐0.10 (‐0.62 to 0.53)	90	‐0.16 (‐0.83 to 0.61)	0.31
Trail Making Test A	76	0.08 (‐1.01 to 1.82)	92	‐0.37 (‐2.08 to 0.50)	0.02*
Trail Making Test B	74	‐0.45 (‐2.37 to 1.04)	90	‐0.49 (‐2.60 to 0.62)	0.30
Cognitive composite score	73	‐0.03 (‐0.90 to 0.72)	90	‐0.41 (‐1.30 to 0.12)	0.02*
* P < 0.05 IQR: interquartile range

Table 1. Summary of findings: Memantine versus placebo

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Table 2. Summary of findings: Goal Management Training versus Brain Health Program versus wait‐listed control

Cognitive performance measure	Goal Management Training		Brain Health Program		Wait‐listed control		P	Goal Management Training		Brain Health Program		Wait‐listed control		P
Cognitive performance measure	N	Domain composite score change post‐training compared to baseline (SD)	N	Domain composite score change post‐training compared to baseline (SD)	N	Domain composite score change post‐training compared to baseline (SD)		N	Domain composite score change at 4‐month follow‐up compared to baseline (SD)	N	Domain composite score change at 4‐month follow‐up compared to baseline (SD)	N	Domain composite score change at 4‐month follow‐up compared to baseline (SD)
Executive composite	10	0.33 (0.54)	6	0.08 (0.43)	4	‐0.44 (0.45)	0.077	10	0.69 (0.51)	6	0.13 (0.50)	3	‐0.07 (0.44)	0.046
Memory composite	10	0.40 (0.84)	6	0.11 (0.91)	4	0.43 (0.76)	0.778	10	1.08 (0.82)	6	0.86 (1.01)	3	0.84 (0.52)	0.842
Processing speed	10	0.44 (0.55)	6	0.47 (0.43)	4	‐0.65 (1.53)	0.071	10	0.54 (0.57)	6	‐0.14 (0.94)	3	‐0.18 (1.03)	0.179
SD: standard deviation P values refer to time‐by‐group interaction (intervention) effects on change compared to baseline, using analysis of variance

Table 2. Summary of findings: Goal Management Training versus Brain Health Program versus wait‐listed control

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Comparison 1. Prevention: Memantine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Cognitive functioning composite score Show forest plot	1		Other data	No numeric data

1.2 Cognitive functioning sub‐tests Show forest plot	1		Other data	No numeric data

1.2.1 Short‐term verbal memory	1		Other data	No numeric data
1.2.2 Long‐term verbal memory (recall)	1		Other data	No numeric data
1.2.3 Long‐term verbal memory (recognition)	1		Other data	No numeric data
1.2.4 Trail making test A	1		Other data	No numeric data
1.2.5 Trail making test B	1		Other data	No numeric data
1.2.6 Verbal fluency	1		Other data	No numeric data
1.3 Adverse events Show forest plot	1	508	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.76, 1.32]

Comparison 1. Prevention: Memantine versus placebo

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Comparison 2. Prevention: d‐threo‐methylphenidate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 General cognitive functioning Show forest plot	1		Other data	No numeric data

2.2 Depression Show forest plot	1		Other data	No numeric data

2.3 Fatigue Show forest plot	1	28	Mean Difference (IV, Fixed, 95% CI)	3.30 [‐10.37, 16.97]

2.4 Quality of life Show forest plot	1		Other data	No numeric data

2.4.1 FACT	1		Other data	No numeric data
2.4.2 Brain subscale	1		Other data	No numeric data

Comparison 2. Prevention: d‐threo‐methylphenidate versus placebo

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Comparison 3. Prevention: Cognitive rehabilitation versus standard care

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Cognitive functioning Show forest plot	1		Other data	No numeric data

3.2 Cognitive functioning sub‐test Show forest plot	1		Other data	No numeric data

3.2.1 Attention	1		Other data	No numeric data
3.2.2 Short‐term verbal memory	1		Other data	No numeric data
3.2.3 Short‐term visual memory	1		Other data	No numeric data
3.2.4 Long‐term verbal/visual memory	1		Other data	No numeric data
3.2.5 Language	1		Other data	No numeric data
3.3 Mood Show forest plot	1		Other data	No numeric data

3.4 Fatigue Show forest plot	1		Other data	No numeric data

3.5 Functional capacity Show forest plot	1	13	Mean Difference (IV, Fixed, 95% CI)	‐8.55 [‐22.57, 5.47]

3.6 Quality of life Show forest plot	1	13	Mean Difference (IV, Fixed, 95% CI)	6.00 [‐21.55, 33.55]

Comparison 3. Prevention: Cognitive rehabilitation versus standard care

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Comparison 4. Amelioration: Methylphenidate versus modafinil

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Cognitive functioning (calculated score) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1.1 Attention (Digit Span)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.38 [0.03, 0.73]
4.1.2 Speed of processing (Digit symbol)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.37 [‐0.30, 1.04]
4.2 Cognitive functioning (timed tasks) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.2.1 Speed of processing (TMTA)	1	23	Mean Difference (IV, Fixed, 95% CI)	‐2.48 [‐4.82, ‐0.14]
4.2.2 Executive function	1	22	Mean Difference (IV, Fixed, 95% CI)	0.69 [‐0.50, 1.88]
4.2.3 Psychomotor functioning (dominant hand)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.61 [‐1.36, 2.58]
4.2.4 Psychomotor functioning (non‐dominant hand)	1	22	Mean Difference (IV, Fixed, 95% CI)	‐5.38 [‐51.16, 40.40]
4.3 Cognitive functioning (total score) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.3.1 Verbal fluency	1	23	Mean Difference (IV, Fixed, 95% CI)	0.33 [‐0.16, 0.82]
4.3.2 Short‐term verbal memory	1	23	Mean Difference (IV, Fixed, 95% CI)	0.42 [‐0.35, 1.19]
4.3.3 Long‐term verbal memory (recall)	1	23	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐2.00, 1.24]
4.3.4 Long‐term verbal memory (recognition)	1	23	Mean Difference (IV, Fixed, 95% CI)	1.62 [‐0.56, 3.80]
4.4 Self‐reported confusion Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	‐1.04 [‐4.76, 2.68]

4.5 Anxiety Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.5.1 STAI State anxiety	1	23	Mean Difference (IV, Fixed, 95% CI)	‐1.35 [‐11.66, 8.96]
4.5.2 STAI Trait anxiety	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.83 [‐22.21, 20.55]
4.5.3 POMS anxiety	1	24	Mean Difference (IV, Fixed, 95% CI)	3.56 [‐0.37, 7.49]
4.6 Depression Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.6.1 BDI‐II	1	24	Mean Difference (IV, Fixed, 95% CI)	0.44 [‐1.93, 2.81]
4.6.2 POMS depression‐dejection	1	24	Mean Difference (IV, Fixed, 95% CI)	0.37 [‐0.48, 1.22]
4.7 Anger Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐5.99, 4.99]

4.8 Fatigue Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.8.1 Brief Fatigue Inventory	1	24	Mean Difference (IV, Fixed, 95% CI)	‐5.20 [‐12.56, 2.16]
4.8.2 POMS‐Fat	1	24	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐1.30, 1.76]
4.9 Sleep Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	‐2.39 [‐6.27, 1.49]

4.10 Activity Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	1.94 [‐1.79, 5.67]

4.11 Quality of life Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	2.71 [‐14.46, 19.88]

Comparison 4. Amelioration: Methylphenidate versus modafinil

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Comparison 5. Amelioration: Donepezil versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Cognitive composite score Show forest plot	1	144	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.05, 0.11]

5.2 Cognitive functioning (timed tasks) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.2.1 Speed of processing	1	145	Mean Difference (IV, Fixed, 95% CI)	‐1.82 [‐11.49, 7.85]
5.2.2 Executive function	1	143	Mean Difference (IV, Fixed, 95% CI)	1.61 [‐15.98, 19.20]
5.2.3 Psychomotor functioning (dominant hand)	1	141	Mean Difference (IV, Fixed, 95% CI)	‐11.93 [‐21.51, ‐2.35]
5.2.4 Psychomotor functioning (non‐dominant hand)	1	142	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐5.21, 5.19]
5.3 Cognitive functioning (total score) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.3.1 Attention (Digit span (total))	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐1.12, 0.80]
5.3.2 Attention (Digit span (backward))	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.01, 0.21]
5.3.3 Attention (Digit Span (forward))	1	145	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.57, 0.69]
5.3.4 Verbal fluency	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.92 [‐3.19, 1.35]
5.3.5 Short‐term verbal memory	1	145	Mean Difference (IV, Fixed, 95% CI)	0.32 [‐0.93, 1.57]
5.3.6 Long‐term verbal memory (recall)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.35 [‐0.36, 1.06]
5.3.7 Long‐term verbal memory (retention)	1	145	Mean Difference (IV, Fixed, 95% CI)	3.96 [‐4.40, 12.32]
5.3.8 Long‐term verbal memory (recognition)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.57 [0.07, 1.07]
5.3.9 Long‐term verbal memory (discrimination)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.94 [0.27, 1.61]
5.3.10 Short‐term visual memory (copy)	1	144	Mean Difference (IV, Fixed, 95% CI)	‐0.69 [‐1.63, 0.25]
5.3.11 Short‐term visual memory (recall)	1	144	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐1.51, 0.51]
5.3.12 Long‐term visual memory (retention)	1	143	Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐1.48, 0.70]

Comparison 5. Amelioration: Donepezil versus placebo

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Comparison 6. Amelioration: Goal management training versus brain health program versus wait‐listed control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Cognitive performance measures: Goal management training versus wait‐list control Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1.1 Executive composite ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	0.77 [0.22, 1.32]
6.1.2 Executive composite ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	0.76 [0.17, 1.35]
6.1.3 Memory composite ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.94, 0.88]
6.1.4 Memory composite ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	0.24 [‐0.54, 1.02]
6.1.5 Processing speed ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	1.09 [‐0.45, 2.63]
6.1.6 Processing speed ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	0.72 [‐0.50, 1.94]
6.2 Cognitive performance measures: Goal management training versus brain health program Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.2.1 Executive composite ‐ immediately post‐training compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.23, 0.73]
6.2.2 Executive composite ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	0.56 [0.05, 1.07]
6.2.3 Memory composite ‐ immediately post‐training compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	0.29 [‐0.61, 1.19]
6.2.4 Memory composite ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐0.73, 1.17]
6.2.5 Processing speed ‐ immediately post‐training compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.51, 0.45]
6.2.6 Processing speed ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	0.68 [‐0.15, 1.51]
6.3 Cognitive performance measures: Brain health program versus wait‐list control Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.3.1 Executive composite ‐ immediately post‐training compared to baseline	1	10	Mean Difference (IV, Fixed, 95% CI)	0.52 [‐0.04, 1.08]
6.3.2 Executive composite ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.44, 0.84]
6.3.3 Memory composite ‐ immediately post‐training compared to baseline	1	10	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐1.36, 0.72]
6.3.4 Memory composite ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.98, 1.02]
6.3.5 Processing speed ‐ immediately post‐training compared to baseline	1	10	Mean Difference (IV, Fixed, 95% CI)	1.12 [‐0.42, 2.66]
6.3.6 Processing speed ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.04 [‐1.35, 1.43]
6.4 Patient‐reported outcome measures: Goal management training versus wait‐list control Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.4.1 Cognitive symptoms composite ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	0.48 [‐0.23, 1.19]
6.4.2 Cognitive symptoms composite ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.24, 0.74]
6.4.3 Emotional functioning composite ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.24, 0.78]
6.4.4 Emotional functioning composite ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.73, 0.65]
6.4.5 Coping/adjusting composite ‐ immediately post‐training compared to baseline	1	14	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.69, 0.83]
6.4.6 Coping/adjusting composite ‐ 4 months compared to baseline	1	13	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.82, 0.44]
6.5 Patient‐reported outcome measures: Goal management training versus brain health program Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.5.1 Cognitive symptoms composite ‐ immediately post‐training compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	‐0.28 [‐0.68, 0.12]
6.5.2 Cognitive symptoms composite ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	‐0.64 [‐1.05, ‐0.23]
6.5.3 Emotional functioning composite ‐ immediately post‐training compared to baseline	1	15	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.51, 0.11]
6.5.4 Emotional functioning composite ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	‐0.29 [‐0.69, 0.11]
6.5.5 Coping/adjustment composite ‐ immediately post‐training compared to baseline	1	15	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.57, 0.43]
6.5.6 Coping/adjustment composite ‐ 4 months compared to baseline	1	16	Mean Difference (IV, Fixed, 95% CI)	‐0.24 [‐0.60, 0.12]
6.6 Patient‐reported outcome measures: Brain health program versus wait‐list control Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.6.1 Cognitive symptoms composite ‐ immediately post‐training compared to baseline	1	10	Mean Difference (IV, Fixed, 95% CI)	0.76 [0.04, 1.48]
6.6.2 Cognitive symptoms composite ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.89 [0.34, 1.44]
6.6.3 Emotional functioning composite ‐ immediately post‐training compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.47 [‐0.04, 0.98]
6.6.4 Emotional functioning composite ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.39, 0.89]
6.6.5 Coping/adjustment composite ‐ immediately post‐training compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.61, 0.89]
6.6.6 Coping/adjustment composite ‐ 4 months compared to baseline	1	9	Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.57, 0.67]

Comparison 6. Amelioration: Goal management training versus brain health program versus wait‐listed control

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