Table 1 Summary of eligible studies on late effects assessed by neuropsychological testing, n = 10 studies

Zając-Spychała et al 2017 Poland [18]

33 (17:16); ALL

Study group:

▪ Group I: HD-MTX (n=22)

▪ Group II: HD-MTX, cRT (n=11; group not included in review)

Control group:

▪ Newly diagnosed ALL (before treatment, no CNS involvement) (n=12)

Group I:

median 5.2 (IQR 4.3-8.2)

Group II:

median 4.9 (IQR 3.9-8.8)

Group I:

median 4.2 (range 2.6-6.0)

Group II:

median 4.8 (range 2.5-6.3)

Follow-up: since end of treatment

Neuropsychological testing: continuous variables

Group I vs. control group:

▪ Memory and attention: 3/7 tests sign. worse in group I

▪ Processing speed: 1/2 tests sign. worse in group I

▪ Executive functions: no sign. difference in 4/4 tests

▪ IQ assessment: no sign. difference

Sherief et al 2018 Egypt [19]

100 (44:56); ALL

Study group:

▪ Group I: No HD-MTX (n=44)

▪ Group II: HD-MTX (n=56) 

≤ 5 (n=46)

> 5 (n=54)

N/A; at least: ≥ 1

Follow-up: since

end of treatment

Neuropsychological testing: continuous variables

Group I vs. II:

▪ IQ assessment (full scale IQ): sign. worse in group II

▪ Verbal IQ subtests: 6/6 tests sign. worse in group II

▪ Performance IQ subtests: 4/6 tests sign. worse in group II

Halsey et al 2011 UK [20]

555 (N/A); ALL

Study group:

▪ Group I (low risk): No HD-MTX (n=197)

▪ Group II (low risk): HD-MTX (n=202)

▪ Group III (high risk):HD-MTX (n=79, not included in review as compared to group IV only)

▪ Group IV (high risk): No HD-MTX, cRT (n=77, group not included in review)

N/A (age at examination: median 4)

N/A; tests after 3 and 5

Follow-up: since

start of therapy

Neuropsychological testing: continuous variables

Group I vs. II:

▪ IQ assessment (full scale IQ): no sign. difference at 3 and 5 years

▪ Verbal IQ subtest: no sign. difference at 3 and 5 years

▪ Performance IQ subtest: no sign. difference at 3 and 5 years

Spiegler et al 2006 Canada [21]

79 (37:42); ALL

Study group:

▪ Group I: HD-MTX (8.0 g/m²/dose) (n=32)

▪ Group II: VHD-MTX (33.6 g/m²/dose) (n=22)

▪ Group III: No HD-MTX, cRT (n=25, group not included in review)

Control group:

▪ Standard scores from each test

Study group:

mean 2.8 ± 1.1

(range 1.0-5.0)

Group I:

mean 2.9 ± 1.0

(range 1.4-4.9)

Group II:

mean 1.9 ± 0.6

(range 1.0-3.4)

Study group:

mean 10.5 ± 2.7

(range 5.1-20.6)

Group I:

mean 9.0 ± 1.9

(range 5.1-13.5)

Group II:

mean 11.8 ± 3.2

(range 5.5-20.6)

Follow-up:

since diagnosis

Neuropsychological testing: continuous variables

Group I vs. II:

▪ Neurocognitive measures: no sign. difference in 18/18 measures in the fields of intelligence, academic achievement, attention and memory (no data shown)

Group I and II (combined) vs. control group:

▪ Neurocognitive measures: 1/18 measure sign. worse in group I/II (field of attention)

Zając-Spychała et al 2018 Poland [22]

78 (46:32); ALL

Study group:

▪ Group I: HD-MTX (2 g/m²/dose) (n=31)

▪ Group II: HD-MTX (5 g/m²/dose) (n=17)

▪ Group III: HD-MTX (5 g/m²/dose), cRT (n=30, group not used in review)

Control group:

▪ Newly diagnosed ALL (before treatment, no CNS in-volvement; matched for age, sex) (n=23)

Study group:

median 11.7

(IQR 1.0-9.3)

Group I:

median 6.2

(range 2.3-17.4)

Group II:

median 8.5

(range 3.3-17.0)

Median 3.8

(range 1.4- 6.3)

Follow up: since

end of treatment

Neuropsychological testing: continuous variables

Group I vs. control group:

▪ Memory and learning: 1/4 measures sign. worse in group I

▪ Processing speed and attention: no sign. difference in 2/2 measures

▪ Executive functions: no sign. difference in 4/4 measures

▪ IQ assessment (full scale IQ): sign. worse in group I

Group II vs. control group:

▪ Memory and learning: 1/4 measures sign. worse in group II

▪ Processing speed and attention: no sign. difference in 2/2 measures

▪ Executive functions: no sign. difference in 4/4 measures

▪ IQ assessment (full scale IQ): sign. worse in group II

Group I vs. II:

▪ No sign. difference between the groups (trend: lower scores in processing speed, attention, visual short-term memory in group II; no data shown)

Edelmann et al 2016 US [23]

80 (46:34); Osteosarcoma

Study group:

▪ Group I: HD-MTX (n=71; n=9 only patient-related outcomes)

Control group:

▪ Healthy controls (matched for age, race, sex) (n=39)

▪ Normative population data (z-scores)

Mean 14.20

Mean 24.70

± 6.60 Follow-up:

since diagnosis

Neuropsychological and emotional testing: continuous variables

Group I vs. control group:

▪ Memory: 2/3 tests sig. worse in group I

▪ Attention: 2/3 tests sig. worse in group I

▪ Processing speed: 4/4 tests sig. worse in group I

▪ Executive function: 1/3 tests sig. worse in group I

▪ Intelligence: 1/2 tests sig. worse in group I

▪ Academics: 1/2 tests sig. worse in group I

▪ Patient reported neurobehavioral functions: 2/8 tests sig. worse in group I

▪ Emotional assessment: 1/3 tests sig. worse (domain: somatization)

Group I vs. population norm:

▪ Memory: 1/3 tests sig. worse in group I

▪ Attention: 2/3 tests sig. worse in group I

▪ Processing speed: 2/4 tests sig. worse in group I

▪ Executive function: 2/3 tests sig. worse in group I

▪ Intelligence: 1/2 tests sig. worse in group I

▪ Academics: 2/2 tests sig. worse in group I

▪ Patient reported neurobehavioral functions: 2/8 tests sig. worse in group I

▪ Emotional assessment: no sig. difference in 3/3 tests

Higher number of HD-MTX courses, higher cumulative dose of HD-MTX, higher median peak HD-MTX concentration, higher median HD-MTX clearance, higher median HD-MTX AUC and higher cumulative HD-MTX AUC:

▪ no sign. association with abnormal neuropsychological and emotional testing (memory, attention, processing speed, executive function, reading, emotional assessment)

Liu et al 2018 US [24]

158 (76:82); ALL

Study group:

▪ Group I: HD-MTX (2.5 g/m²/dose) (n=90)

▪ Group II: HD-MTX (5.0 g/m²/dose) (n=68)

Control group:

▪ nrv (z-scores)

Mean 6.6 ± 4.5

Mean 7.6 ± 1.7

Follow-up:

since diagnosis

Neuropsychological testing: continuous variables

Group I and II (combined) vs. control group:

▪ Attention: 1/7 tests sign. worse in group I/II

▪ Processing speed: 3/7 tests sign. worse in group I/II

▪ Executive function: 4/10 tests sign. worse in group I/II

Higher dose of HD-MTX (AUC):

▪ sign. association with attention problems (1/2 assessments)

▪ sign. association with processing speed problems (2/3 assessments)

▪ sign. association with executive function problems (1/5 assessments)

Fellah et al 2019 US [25]

165 (85:80); ALL

Study group:

▪ Group I: HD-MTX (2.5 g/m²/dose) (n=93)

▪ Group II: HD-MTX (5.0 g/m²/dose) (n=72)

Control group:

▪ nrv (z-scores)

Mean 6.7 ± 4.4

Mean 7.7 ± 1.7

Follow-up:

since diagnosis

Neuropsychological testing: continuous variables

Group I and II (combined) vs. control group:

▪ Memory: 1/2 tests sig. worse in group I/II

▪ Attention: no sig. difference in 4/4 tests]

▪ Processing speed: 3/7 tests sig. worse in group I/II

▪ Executive function: 4/9 tests sig. worse in group I/II

▪ Intelligence: 1/5 tests sig. worse in group I/II

Higher dose of HD-MTX (AUC):

▪ sign. association with processing speed problems (no data shown)

▪ sign. association with executive function problems (1/9 tests)

Jansen et al 2008 The Netherlands [26]

49 (29:20); ALL

Study group:

▪ Group I: HD-MTX (2 g/m²/dose) (n=32)

▪ Group II: HD-MTX (3 g/m²/dose) (n=17)

Control group:

▪ Healthy siblings (matched for age) (n=28)

Median 6.4

(range 4.0-11.8)

Median 4.6

(range 4.1-4.9)

Follow-up:

since diagnosis

Neuropsychological testing: continuous variables

Group I and II (combined) vs. control group:

▪ Learning and memory: no sign. difference in 3/3 assessments (no data shown)

▪ Sustained attention and speed: no sign. difference in 2/2 assessments (no data shown)

▪ Executive functioning: no sign. difference in 2/2 assessments (no data shown)

▪ Visual-motor and fine-motor function: 1/4 assessments sign. worse in group I/II, 2/4 assessments no sig. difference, 1/4 assessments no comparison done (no data shown)

Jacola et al 2016 US [27]

211 (107:104); ALL

Study group:

▪ Group I: HD-MTX (2.5 g/m²/dose) (n=115)

▪ Group II: HD-MTX (5.0 g/m²/dose) (n=96)

Control group:

▪ nrv

Range 1.0-18.0

< 5.0 (n=102)

≥ 5.0 (n=109)

N/A

tests after 2

Follow-up: since

end of treatment

Neuropsychological testing: continuous variables

Group I and II (combined) vs. control group:

▪ Sustained attention: sign. more below average performance in group I/II

▪ Verbal learning: no sign. difference in 4/4 tests (no data shown)

▪ Wechsler scales: no sign. difference in 3/3 tests (no data shown)

▪ Academics: no sign. difference in 3/3 tests (no data shown)

Group I vs. control group:

▪ Sustained attention: 5/5 tests sign. worse in group I

▪ Verbal learning: 1/4 tests sign. worse in group I

▪ Wechsler scales: 1/3 tests sign. worse in group I

▪ Academics (WIAT): 3/3 tests sign. worse in group I

Group II vs. control group:

▪ Sustained attention: 4/5 tests sign. worse in group II

▪ Verbal learning: 1/4 tests sign. worse in group II

▪ Wechsler scales: 3/3 tests sign. worse in group II

▪ Academics: 1/3 tests sign. worse in group II

Group I vs. II:

▪ Sustained attention: no sign. difference in 5/5 tests

▪ Verbal learning: no sign. difference in 4/4 tests

▪ Wechsler scales: 1/3 tests sign. worse in group II

▪ Academics: 3/3 tests sign. worse in group II

Group I vs. II comparing percentage below average performance:

▪ Sustained attention: no sign. difference in 5/5 tests

▪ Verbal learning: 1/4 tests with more below average in group II; OR 0.4   (95%CI 0.2-1.0)

▪ Wechsler scales: 3/3 tests with more below average in group II

 Working memory: OR 0.4 (95%CI 0.2-0.9)

 Processing speed: OR 0.1 (95%CI 0.0-0.6)

 Intelligence: OR 0.3 (95%CI 0.1-0.6)

▪ Academics: 3/3 tests with more below average in group II

 Math: OR 0.4 (95%CI 0.2-0.8)

 Reading: OR 0.2 (95%CI 0.1-0.6)

 Spelling: OR 0.4 (95%CI 0.2-0.8)

HD-MTX per 5 g/m²

▪ Subscales of sustained attention, verbal learning, Wechsler Scales, academics: no sign. association of HD-MTX with adverse results