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

From: Late effects of high-dose methotrexate treatment in childhood cancer survivors—a systematic review

First author
Year
Country
Final cohort size (male:female), diagnosis and cohort
description
Age at diagnosis
[years]
Follow-up
[years]
Outcome variables, data type and effect of HD-MTX
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
  1. ALL acute lymphoblastic leukemia, AUC area under the curve, CI confidence interval, CNS central nervous system, cRT cranial radiotherapy, HD-MTX high-dose methotrexate, IQR interquartile range, n number, N/A missing information, nrv normal reference values, OR odds ratio, sign. significant(ly), VHD-MTX very high-dose methotrexate, vs. versus