Table 4.

Main message of the studies categorized by type of radiotherapy

RT type	Authors	Patients, N	Time points NCF assessed in months after RT	Definition of cognitive change	Main message
WBRT	Mehta et al. [7, 18, 38, 74]	208	T0	≤2 SD change in average Z-score	T3: Most patients deteriorate on fine motor coordination and least patients on verbal fluency
		135	T1
		63–75*	T2		T4: Significant deterioration compared to T0 on L&M and verbal fluency
		43–46*	T3		T15: Significant improvement compared to T0 on verbal fluency, fine motor coordination, and information processing speed
		9	T4 T5 T6 T9 T12 T15 T18
	Gondi et al. [26]	100	T0	RCI	T2: 7–18% mean decline from T0 in L&M performance
		53	T2		T4: In a subset of 33 patients with T0 MRI, the change in L&M performance was correlated with BMs volume (immediate and delayed recall), age (immediate recall), and volume of white matter injuries pre-treatment (recognition) T6: Certain aspects of L&M declined (delayed recall), while others remained stable (immediate recall and recognition). The mean relative decline from T0 to T6 was 0–3%
		42	T4
		29	T6
	Saito et al. [28]	34	T0	RCI	T4: L&M deteriorated significantly compared to T0 in those who only completed
		34	T4		T0 and T4 assessments. In total, 27–33% of the patients had deteriorated
		19	T8		T8: On an average, stable cognitive performance was observed on L&M in subgroup completing assessments at all 3 time points. Of this subgroup, 11–26% had deteriorated L&M performance compared to baseline
WBRT		109	T0	RCI	T3: 22–38% of the patients deteriorated on overall cognitive performance, with greatest deterioration on L&M (22–37%), EF (38%) and verbal fluency (32%)
		87–89*	T3
		61–64*	T5		T5: 40–55% of the patients deteriorated on at least one cognitive task, with greatest deterioration on L&M (52–55%) and verbal fluency (53%) T7: 47–61% of the patients deteriorated on at least one cognitive task, with greatest deterioration on EF (61%) and verbal fluency (59%)
		34–36*	T7
	Deng et al. [35]	81	T0	N.A.	T1: Significantly decreased performance compared to T0 on global cognitive performance, attention, verbal fluency, and event-based prospective memory. Stable performance on time-based prospective memory
		81	T1
	Cheng et al. [34]	117	T0	RCI	T3: 19% of the patients deteriorated on L&M performance
		91	T1		T6: 35% of the patients deteriorated on L&M performance
		54	T2 T3 T4 T5 T6
	Zhan et al. [39]	33	T0	RCI	T3: Deteriorated cognitive performance was found on L&M, EF, and verbal fluency in 19%, 29%, and 28% of the patients, respectively
		29–31*	T3
		26–29*	T6		T6: Deteriorated cognitive performance was found on L&M, EF, and verbal fluency in 48%, 48%, and 50% of the patients, respectively T9: Deteriorated cognitive performance was found on L&M, EF, and verbal fluency in 50%, 58%, and 57% of the patients, respectively
		22–26*	T9
	Zhu et al. [40]	47	T0	≤1 SD decline from the mean	T3: Compared to T0, L&M performance declined in 17% of the patients on delayed recall with a mean decline of 11%. No significant changes were found on the other cognitive tasks, but there were large variations
		18	T3
		8	T6
		5	T9		T6: Mean L&M performance (delayed recall) recovered to pre-treatment values
			T12
WBRT	Westover et al.	20	T0	N.A.	T4: Patients receiving WBRT deteriorated significantly compared to T0 on L&M (delayed recall). Additional analysis showed only patients with a brain edema volume ≥16.8 cc. Decreased on L&M (delayed recall) and EF
	[41]	17	T4
	Onodera et al.	14	T8
	[25]	9	T12		T8: Patients receiving WBRT deteriorated significantly compared to T0 and T4 on L&M (immediate recall) Improvements in immediate and delayed recall at T8 compared to T4 were only observed in patients with a <4.0 cc total volume of BM at T0 T12: In the subgroup of patients followed for at least 12 months, L&M (delayed recognition) had significantly declined compared to T0 at both T4 and T12. This subgroup also had significantly declined EF at T4 compared to T0, with a similar trend at T12. Additionally, L&M (immediate recall) had returned to baseline values at T12 after a significant improvement at T8 No changes in verbal fluency, information processing speed, or on cognitive screening measure at any time point
SRS		7	T0	N.A.	T4–12: SRS group had no change in cognitive performance for any tested cognitive construct over the entire study period
		5 5 4	T4 T8 T12
		15	T0	RCI	1: All patients declined on ≥1 neuropsychological test and 54% on ≥2 tests, with decline in L&M (54%) and fine motor coordination (46%) most common.
		13	T1
		5	T2		Improvements were also observed, mostly on EF (38%), verbal fluency (15%), fine motor coordination (15%), and information processing speed (15%)
			T3
			T4		T7–9: Stable or improved cognitive performance was found for 80% of the patients for L&M and 60.0% for EF and fine motor coordination
			T5 T7–9 T10–12
	Chang et al. [29]	30	T0	RCI	T4: Most cognitive decline on tests for L&M (20% of the patients on total recall).
		20	T1		The mean posterior probability of decline was 24% for total recall, 6% for delayed recall end 0% for delayed recognition. Analysis were also performed for other cognitive tests but might have been underpowered since the trial was stopped prematurely due to significant larger probability of decline on L&M (total recall) after 4 months in the SRS + WBRT versus the SRS alone group
			T2
			T4
			T6
			T12
			T15		T6: The mean posterior probability of decline on total recall was 8%
			T18
SRS	Chang et al. [31]	111	T0	≥1 SD	T3: 64% of the patients showed cognitive deterioration on ≥1 test compared to T = 0. Most patients deteriorated on L&M (recognition) performance (23%) and information processing speed (19%) and least on verbal fluency (2%)
		63	T1.5
		10–12*	T3
		12–14*	T6		T6: In those patients surviving at least 12 months, 50% deteriorated on at least 1 test compared to T = 0. Most patients deteriorated on L&M (delayed recall) performance (33%) and none deteriorated on information processing speed T9: In those patients surviving at least 12 months, 50% deteriorated on at least 1 test compared to T = 0. Most patients deteriorated on L&M (delayed recall and discrimination index) performance (both 23%) and none on verbal fluency T12: In those patients surviving at least 12 months, 60% deteriorated on at least 1 test compared to T = 0. Most deteriorated on L&M (delayed recall) performance (20%) and none on verbal fluency
		9–10*	T9
			T12
	Brown et al. [32]	97	T0	≤1.5 SD mean of healthy controls	T6: The majority of the patients maintained their pre-treatment levels of cognitive performance over the entire study period. Only verbal fluency performance showed trend towards improvement
		39	T3
		29	T6
	Habets et al. [30, 43]	38	T0	RCI	T3: Compared to T0, L&M performance declined in 13%, 16%, and 19% of the patients on immediate recall, recognition, and delayed recall. The mean decline varied between 10 and 14%
		32	T3
		26	T6
		21	T12		T6: Compared to T0, L&M performance declined in 12%, 15% and 15% of the patients on immediate recall, recognition and delayed recall The mean decline varied between 5 and 9% T12: Compared to T0 L&M performance declined in 5%, 10% and 14% of the patients on immediate recall, recognition and delayed recall. The mean decline varied between 2 and 5%

T, time point in months after radiotherapy; N.A., not available; NCF, neurocognitive functioning; RCI, reliable change index; RT, radiotherapy; SD, standard deviations; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy; L&M, learning and memory; EF, executive function. * Ranges in patient numbers are caused by different numbers of patients completing the different cognitive tests during the study-procedures.