Keywords
Acute lymphoblastic leukemia - BFM-95 protocol - central nervous system prophylactic
treatment - chemotherapy - childhood cancer - cranial irradiation - neuropsychological
functioning
Introduction
Leukemia is the most common childhood cancer in India, with a relative proportion
of 25%–40% of all cancers.[1]
[2] Acute lymphoblastic leukemia (ALL) accounts for 65%–85% of all leukemia cases reported.[1]
[3] Cure rates of childhood ALL have improved from virtually 0 in the 1950s to 90% currently
in Western countries.[4] Overall survival outcomes at tertiary cancer centers in India (Mumbai, Chennai,
and Bangalore) range from 65% to 70%.[5] Central nervous system (CNS) prophylaxis is a vital part of ALL treatment as it
decreases the risk of CNS relapse and is greatly responsible for the remarkable increase
in survival rates.[5]
[6]
[7]
[8]
[9] Intrathecal methotrexate (IT-MTX), intravenous high-dose methotrexate (HD-MTX),
cranial radiation therapy (CRT), triple IT chemotherapy, or a combination of these
modalities is commonly used to treat ALL.[10]
[11] The use of CRT, HD-MTX, or IT-MTX is based on patient risk stratification. At present,
HD-MTX is only administered to patients with T-cell ALL or high-risk patients with
B-cell ALL, and CRT is reserved for patients with overt CNS disease.[11]
[12]
[13] In the past, most patients in India received CRT as the treatment was not risk stratified;
however, most centers have now moved toward risk-adapted therapy.[5]
[6]
[7]
[8]
[9]
[14]
With the rate of ALL survivors increasing in India, the need to study the effects
of ALL treatment protocol including CRT on neurocognitive functioning is increasing.
The modified BFM-95 protocol is used at the Cancer Institute (Chennai) which includes
a combination of intravenous MTX, IT-MTX, and CRT. No prospective studies on the effect
of any of these protocols have been conducted in India. Therefore, this prospective
study was conducted to evaluate the effect of the modified BFM-95 protocol on neurocognitive
functioning in children with ALL.
Methods
The study was conducted between 2011 and 2015. Ethical clearance was obtained before
the initiation of the study. Children aged 6–15 years, who received the diagnosis
of ALL- and CNS-directed therapy including HD-MTX, IT-MTX, and CRT, were included
in the study. Furthermore, the children had to be attending regular school for inclusion
in the study. Children with a history of any neurological disorder, psychiatric disorder,
severe head injuries, disease relapse, and secondary malignancy at the time of assessment
were excluded from the study. The control group included healthy children from local
communities who attended regular school and matched the patients with ALL in age,
sex, and socioeconomic status. The details of the sample recruited are presented in
[Figure 1]. Children with ALL were from different geographical locations of Tamil Nadu and
Andhra Pradesh, and healthy children were from Chennai.
Figure 1: Flowchart of sample recruitment
Procedures and tools used
Written informed consent was obtained from the parents of children aged <12 years.
A total of five neuropsychological assessments were completed at different phases
of the modified BFM-95 treatment protocol.
The details of the tools used in the study are summarized in [Table 1]. Briefly, for the battery of tests used to assess neurocognitive function, higher
scores indicated better performance. Some tests considered processing time and evaluated
the performance level. T2-weighted, axial three-dimensional, spoiled gradient, and
high-resolution MR images were collected using a 1.5 T MRI scanner to examine the
neuroanatomical structures.
Table 1
Neurocognitive test battery and MRI used and its outcome measures
|
Tools name
|
Author and year
|
Functions assessed
|
|
MISC - Malin’s Intelligence Scale for Indian Children; MRI - Magnetic resonance image;
WISC - Wechsler Intelligence Scale for Children; NIMHANS - National Institute of Mental
Health and Neurosciences; PIQ - Performance intelligence quotient; CT - Color Trails
Test
|
|
MISC - An Indian adaptation of the WISC
|
Malin (1969)[15]
|
PIQ
|
|
Sub tests of MISC
|
|
|
|
Picture completion
|
|
Visuo-conceptual
|
|
Block design
|
|
Visuospatial
|
|
Coding
|
|
Processing speed
|
|
Object assembly
|
|
Perceptual organization
|
|
Maze
|
|
Planning and fine motor
|
|
The NIMHANS neuropsychological battery for children
|
Kar et al, (2004)[16]
|
|
|
Sub tests of the NIMHANS battery
|
|
|
|
Finger tapping test
|
|
Motor speed
|
|
Color cancellation test
|
|
Sustained attention
|
|
CT
|
|
Focused attention
|
|
Token test
|
|
Verbal comprehension
|
|
Verbal n-back test
|
|
Verbal working memory
|
|
Visuospatial span test
|
|
Visuospatial working memory
|
|
Auditory verbal learning test
|
|
Verbal learning and Memory
|
|
Memory for design test
|
|
Visual learning and Memory
|
|
MRI
|
|
Neuroanatomical structure
|
The baseline assessment was completed immediately after the initiation of the induction
phase when the patient's general health condition is stable. Most children with ALL
presented with poor general health; therefore, the first phase of chemotherapy, which
included two or three doses of IT-MTX chemotherapy, was commenced immediately after
diagnosis (on days 1, 7, and 15). The second and third assessments were conducted
at the end of the re-induction I and re-induction II treatment phases, respectively.
During the third assessment, the patients had completed CNS direct radiation therapy
(1800 cGy). The fourth assessment was completed immediately after the commencement
of the maintenance phase, which was 1 year from the time of diagnosis. The fifth assessment
was completed at the end of the maintenance phase, which was 2 years from the time
of diagnosis. The details of the assessment interval between the different phases
of the modified BFM-95 protocol are presented in [Figure 2]. Routine treatment, investigations, and other medical procedures were not affected
during the study period.
Figure 2: Assessment interval between the different phases of the modified BFM-95
protocol
All the patients included in the study who presented for the fourth assessment (n = 25) underwent a contrast-enhanced MRI (brain) scan. Only eight children with ALL
who were suspected to have neurotoxicity underwent MRI during the induction phase.
MRI was not performed for other patients.
Baseline assessment for the healthy children was completed at the time of recruitment
of the children with ALL, and postassessment was completed during the fifth assessment
period of children with ALL, which was 2 years from the baseline assessment. The assessments
were carried out by the researcher who has trained in neuropsychological assessments
at the National Institute of Mental Health and Neuroscience, Bangalore. The total
duration of the assessments was approximately 3–4 h. To overcome the effect of fatigue,
the tests were administered in 1.5-h sessions with at least one 5–15 min break.
Statistical analysis
Descriptive statistics were used to summarize demographic variables and clinical variables.
Chi-square and independent sample t-tests were performed to find the difference in the demographic variables and neurocognitive
functions between children with ALL and healthy children. General linear model one-way
repeated measures analysis of variance (ANOVA) used to test for change over time (baseline,
intensive phase treatments, and maintenance) in performance on the neurocognitive
measures. Pairwise comparisons were calculated using the Bonferroni correction to
evaluate whether differences in outcome scores at different measurements were significant.
Statistical analyses were performed with the IBM Corporation. Released 2010. IBM SPSS
Statistics for Windows, Version 19.0. (Armonk, New York: IBM Corporation) with the
alpha level set to 0.05 for all analyses.
Results
Demographic and clinical characteristics of children with ALL and demographic characteristics
of healthy children included in the study are summarized in [Table 2]. There was no significant difference based on age, sex, education, socioeconomic
status, family type, and parents' literacy and occupation between children with ALL
and healthy children. In the experimental group, 52% of the children born to parents
from a consanguineous marriage, whereas it was 10.9% in the control group, and the
difference was statistically significant. The mean age at the time of baseline assessment
was 8.76 ± 2.26 years for children with ALL and 9.42 ± 2.07 years for healthy children.
The mean age of children at the time of final assessment was 10.76 ± 2.26 years for
children with ALL and 11.42 ± 2.07 years for healthy children. Of the children with
ALL, 64% were male, and of the healthy children, 56.4% were male. Clinical evaluation
showed that most children with ALL were presented with high risk (56%) or intermediate
risk (40%). Most children (76%) had T-cell immunophenotype. Neurotoxicity was observed
in 24% of the children with ALL.
Table 2
Demographic and clinical characteristics of children with acute lymphoblastic leukemia
and demographic characteristics of healthy children
|
Variables
|
Children with ALL (n=25), n (%)
|
Healthy children (n=55), n (%)
|
t/χ2
|
P
|
|
*t-test. Significance level at 0.05. χ2 - Chi-square test; ALL - Acute lymphoblastic leukemia; SD - Standard deviation; CVT
- Cerebral venous thrombosis
|
|
Age in years at the time of first assessment (baseline)
|
|
|
|
|
|
Mean±SD
|
8.76±2.26
|
9.42±2.07
|
1.28*
|
0.20
|
|
Range
|
6-13
|
6-13
|
|
|
|
Age in years at the time of final assessment (final)
|
|
|
|
|
|
Mean±SD
|
10.76±2.26
|
11.42±2.07
|
1.25*
|
0.21
|
|
Range
|
8-15
|
8-15
|
|
|
|
6-10 years
|
20 (80)
|
32 (58.2)
|
|
|
|
11-15 years
|
5 (20)
|
23 (41.8)
|
|
|
|
Gender
|
|
|
|
|
|
Male
|
16 (64)
|
31 (56.4)
|
0.41
|
0.52
|
|
Female
|
9 (36)
|
24 (43.6)
|
|
|
|
Education in years (baseline)
|
|
|
|
|
|
Mean±SD
|
3.92±2.21
|
4.58±2.32
|
1.42*
|
0.16
|
|
Range
|
1-8
|
1-8
|
|
|
|
Handedness
|
|
|
|
|
|
Right hand
|
25
|
55
|
|
|
|
Mother tongue
|
|
|
|
|
|
Tamil
|
18(72)
|
55
|
|
|
|
Income (monthly income in Rupees) (INR)
|
|
|
|
|
|
<5000
|
18(72)
|
36 (65.5)
|
1.40
|
0.49
|
|
5000-10,000
|
5 (20)
|
17 (30.9)
|
|
|
|
>10,000
|
2 (8)
|
2 (3.6)
|
|
|
|
Family type
|
|
|
|
|
|
Joint family
|
12 (48)
|
17 (30.9)
|
2.80
|
2.46
|
|
Nuclear family
|
13(52)
|
38 (69.1)
|
|
|
|
Consanguineous marriage
|
|
|
|
|
|
Yes
|
13(52)
|
6 (10.9)
|
16.02
|
0.00*
|
|
Literacy
|
|
|
|
|
|
Father
|
|
|
|
|
|
Schooling
|
16 (64)
|
41 (74.5)
|
3.79
|
0.15
|
|
Graduate
|
5 (20)
|
12 (21.8)
|
|
|
|
Illiterate
|
4 (16)
|
2 (3.6)
|
|
|
|
Mother
|
|
|
|
|
|
Primary
|
17 (68)
|
49 (89.1)
|
5.29
|
0.07
|
|
Graduate
|
4 (16)
|
3 (5.5)
|
|
|
|
Illiterate
|
4 (16)
|
3 (5.5)
|
|
|
|
Occupation
|
|
|
|
|
|
Father
|
|
|
|
|
|
Unskilled
|
11 (44)
|
20 (36.4)
|
0.55
|
0.75
|
|
Semiskilled
|
6 (24)
|
13 (23.6)
|
|
|
|
Skilled
|
8 (32)
|
22 (40)
|
|
|
|
Mother
|
|
|
|
|
|
Homemaker
|
17 (68)
|
29 (52.7)
|
5.91
|
0.11
|
|
Unskilled
|
5 (20)
|
20 (36.4)
|
|
|
|
Semiskilled
|
3 (12)
|
2 (3.6)
|
|
|
|
Skilled
|
-
|
4 (7.3)
|
|
|
|
Risk stratification
|
|
|
|
|
|
Low
|
1 (4)
|
|
|
|
|
Intermediate
|
10 (40)
|
|
|
|
|
High
|
14 (56)
|
|
|
|
|
Immunophenotype
|
|
|
|
|
|
T-cell
|
19(76)
|
|
|
|
|
B-cell
|
6 (24)
|
|
|
|
|
Neurotoxicity
|
|
|
|
|
|
Seizure
|
2 (8)
|
|
|
|
|
CVT
|
1 (4)
|
|
|
|
|
Meningitis
|
1 (4)
|
|
|
|
|
Headache
|
2 (8)
|
|
|
|
|
No neurotoxicity
|
19(76)
|
|
|
|
Changes in neurocognitive performance scores of children with acute lymphoblastic
leukemia
The results from the general linear model for repeated measures ANOVA and within-subjects
contrast are shown in [Table 3]. There was a significant change in mean scores in overall performance intelligence
quotient (PIQ), visuospatial ability, processing speed, verbal retention, learning
(verbal and visual), memory (visual immediate and delay), motor speed (right and left
hand), focused attention, and executive function (visuospatial working memory-forward)
across the five assessments. Mean scores for overall PIQ, visuospatial ability, processing
speed, and verbal retention decreased significantly after the third, fourth, and fifth
assessments as compared to the scores after the first and second assessments. However,
the mean scores for verbal retention, learning (verbal and visual), memory (visual
immediate and delay), motor speed (right and left hand), focused attention, and executive
function (visuospatial working memory-forward) increased from baseline to the subsequent
assessments. No significant difference was observed in the neurocognitive functions
such as visuo-conceptual ability, perceptual organization, planning and fine motor
skills, immediate verbal memory, delayed verbal memory, sustained attention, verbal
working memory (n-back 1 and 2), visuospatial working memory (backward), and verbal
comprehension.
Table 3
Mean, standard deviation, and F and P values of neurocognitive assessment scores of children with acute lymphoblastic leukemia
|
Neurocognitive functions
|
Mean±SD
|
F
|
P
|
η
2
|
|
First assessment
|
Second assessment
|
Third assessment
|
Fourth assessment
|
Fifth assessment
|
|
#Score indicates time in seconds (as lesser the time, better the performance); *P<0.05, **P<0.01. ALL - Acute lymphoblastic leukemia; SD - Standard deviation; PIQ - Performance
intelligence quotient; RH - Right hand; LH - Left hand; CT-A - Color Trails Test A;
CT-B - Color Trails Test B; NB 1 - N-back test 1; NB 2 - N-back test 2; VSWM-F - Visuospatial
working memory-forward; VSWM-B - Visuospatial working memory-backward; SD - Standard
deviation; VW - Verbal working memory
|
|
Overall PIQ
|
108.93±12.66
|
111.27±12.04
|
108.60±12.45
|
104.44±11.90
|
97.63±10.18
|
13.85
|
0.01**
|
0.74
|
|
Visuo-conceptual
|
111.00±21.13
|
110.24±17.68
|
108.68±17.68
|
108.04±12.48
|
103.40±16.34
|
1.58
|
0.84
|
0.15
|
|
Visuospatial
|
116.16±24.63
|
117.56±20.53
|
112.44±22.78
|
105.88±20.93
|
103.24±22.59
|
4.60
|
0.01**
|
0.37
|
|
Processing speed
|
111.24±21.72
|
113.32±20.31
|
112.68±18.57
|
107.40±16.61
|
92.92±15.12
|
10.61
|
0.01**
|
0.56
|
|
Perceptual organization
|
98.04±24.03
|
100.04±24.88
|
93.72±18.33
|
94.88±22.10
|
89.12±16.14
|
1.40
|
0.23
|
0.16
|
|
Planning and fine motor
|
110.00±10.41
|
115.36±17.93
|
110.72±19.61
|
109.76±18.55
|
105.80±20.07
|
1.32
|
0.26
|
0.19
|
|
Verbal retention
|
103.55±16.47
|
91.30±14.55
|
96.74±12.13
|
90.73±10.82
|
92.10±11.44
|
4.31
|
0.01**
|
0.30
|
|
Motor speed (RH)
|
32.22±5.62
|
34.45±6.17
|
35.13±5.74
|
37.24±5.66
|
40.10±8.79
|
23.59
|
0.01**
|
0.75
|
|
Motor speed (LH)
|
27.06±5.55
|
29.44±6.50
|
29.70±5.75
|
31.31±6.13
|
33.48±6.76
|
16.15
|
0.01**
|
0.72
|
|
Verbal learning
|
49.92±8.21
|
51.96±9.74
|
52.64±9.06
|
54.24±10.29
|
58.32±8.55
|
10.46
|
0.01**
|
0.58
|
|
Verbal immediate memory
|
10.76±2.52
|
10.80±2.54
|
11.28±2.03
|
11.48±2.20
|
11.64±1.97
|
1.41
|
0.23
|
0.18
|
|
Verbal delayed memory
|
11.44±2.27
|
10.84±2.46
|
11.60±2.25
|
11.92±2.08
|
12.00±2.36
|
1.86
|
1.22
|
0.26
|
|
Visual learning
|
69.20±11.78
|
69.72±11.98
|
70.16±12.08
|
72.48±10.82
|
74.24±7.49
|
4.26
|
0.01**
|
0.30
|
|
Visual immediate memory
|
9.84±3.21
|
10.56±2.73
|
10.80±2.91
|
10.68±2.49
|
11.24±3.12
|
2.66
|
0.03*
|
0.30
|
|
Visual delayed memory
|
9.76±3.16
|
9.88±3.05
|
10.28±2.82
|
10.52±2.38
|
11.72±3.00
|
9.07
|
0.01**
|
0.62
|
|
Sustained attention#
|
91.20±36.72
|
82.52±36.93
|
78.80±23.79
|
75.88±21.64
|
77.56±24.77
|
2.31
|
0.06
|
0.21
|
|
Focused attention (CT-A)#
|
121.96±71.70
|
101.84±56.39
|
92.88±51.79
|
85.52±48.60
|
79.32±32.81
|
7.30
|
0.01**
|
0.39
|
|
Focused attention (CT-B)#
|
240.08±137.42
|
212.64±130.36
|
193.12±72.96
|
160.24±51.66
|
160.68±71.88
|
6.52
|
0.01**
|
0.65
|
|
VW memory (NB 1)
|
8.28±0.97
|
8.20±1.00
|
8.04±1.05
|
8.16±0.74
|
8.16±1.34
|
0.27
|
0.89
|
0.05
|
|
VW memory (NB 2)
|
10.48±2.48
|
10.24±2.52
|
10.12±2.4
|
9.80±2.17
|
10.20±1.84
|
0.47
|
0.75
|
0.10
|
|
VSWM-F
|
4.24±0.83
|
4.08±0.99
|
4.08±1.07
|
4.52±0.50
|
4.64±0.70
|
3.78
|
0.01**
|
0.32
|
|
VSWM-B
|
2.56±1.66
|
2.48±1.71
|
2.32±1.54
|
2.42±1.55
|
2.56±1.50
|
0.28
|
0.88
|
0.05
|
|
Verbal comprehension
|
31.86±5.05
|
31.86±4.26
|
31.58±3.33
|
31.52±3.27
|
32.02±3.53
|
0.15
|
0.96
|
0.01
|
The results of Bonferroni pairwise comparison analyses are shown in [Table 4]. Overall PIQ, visuospatial ability, processing speed, and verbal retention decreased
gradually overtime, whereas a significant difference was observed between the fourth
and fifth assessments in comparison with the other assessments. However, motor speed,
verbal learning, visual delayed memory, and focused attention were found to steadily
increase over time. Significant differences were observed in motor speed across the
assessments; differences in other domains were pronounced in the fourth and fifth
assessments.
Table 4
Pairwise comparisons between the five assessments on neurocognitive functions in children
with acute lymphoblastic leukemia (P values)
|
Functions Neurocognitive functions
|
First versus second
|
First versus third
|
First versus fourth
|
First versus fifth
|
Second versus third
|
Second versus fourth
|
Second versus fifth
|
Third versus fourth
|
Third versus fifth
|
Fourth versus fifth
|
|
#Score indicates time in seconds (as time taken reduces performance increases). Significant
level at 0.05. PIQ - Performance intelligence quotient; RH - Right hand; LH - Left
hand; CT-A - Color Trails Test A; CT-B - Color trails test B
|
|
Overall PIQ
|
|
|
|
0.001
|
|
0.005
|
0.001
|
|
0.001
|
0.008
|
|
Visuospatial
|
|
|
|
|
|
0.041
|
0.031
|
|
|
|
|
Processing speed
|
|
|
|
0.005
|
|
|
0.001
|
|
0.001
|
0.002
|
|
Verbal retention
|
|
|
0.051
|
|
|
|
|
|
|
|
|
Motor speed (RH)
|
0.001
|
0.001
|
0.001
|
0.001
|
|
0.004
|
0.001
|
|
0.003
|
|
|
Motor speed (LH)
|
0.001
|
0.047
|
0.001
|
0.001
|
|
|
0.004
|
|
0.009
|
|
|
Verbal learning
|
|
|
|
0.001
|
|
|
0.002
|
|
0.011
|
|
|
Visual delayed memory
|
|
|
|
0.001
|
|
|
0.002
|
|
0.014
|
|
|
Focused attention (CT-A)#
|
|
|
0.023
|
0.011
|
|
|
|
|
|
|
|
Focused attention (CT-B)#
|
|
|
0.023
|
0.012
|
|
|
|
0.009
|
0.002
|
|
Comparison of neurocognitive function of children with acute lymphoblastic leukemia
and healthy controls
The results were analyzed using the independent t-test and are summarized in [Table 5]. At baseline, the results revealed no significant difference between children with
ALL and healthy children except for verbal immediate memory and visual delayed memory.
At postassessment, the results showed a significant difference in PIQ, visuo-conceptual
ability, visuospatial ability, processing speed, perceptual organization, planning
and fine motor skills, verbal comprehension, verbal working memory, visuospatial working
memory, verbal immediate memory, verbal delayed memory, and visual immediate memory;
no significant difference was observed in motor speed (left and right hand), learning
(verbal and visual), visual delayed memory, sustained attention, and focused attention
(color trails test A). The results show that children with ALL had poorer scores than
healthy children on most of the neurocognitive function at postassessment (fifth assessment).
Table 5
Comparison of baseline and postassessment scores of children with acute lymphoblastic
leukemia and healthy children
|
Neurocognitive functions
|
Baseline assessment
|
Postassessment
|
|
Mean±SD
|
t
|
P
|
Mean±SD
|
t
|
P
|
|
Children with ALL
|
Healthy children
|
Children with ALL
|
Healthy children
|
|
#Score indicates time in seconds (as time taken reduces performance increases); *P<0.05; **P<0.01. ALL - Acute lymphoblastic leukemia; SD - Standard deviation; PIQ - Performance
intelligence quotient; RH - Right hand; LH - Left hand; CT-A - Color Trails Test A;
CT-B - Color Trails Test B; NB 1 - N-back test 1; NB 2 - N-back test 2; VSWM-F - Visuospatial
working memory-forward; VSWM-B - Visuospatial working memory-backward; VW - Verbal
working memory
|
|
Overall PIQ
|
108.93±12.66
|
110.95±10.80
|
0.73
|
0.46
|
97.63±10.18
|
118.32±5.85
|
11.5
|
0.01*
|
|
Visuo-conceptual
|
111.00±21.32
|
113.80±15.47
|
0.66
|
0.50
|
103.40±16.34
|
123.40±10.15
|
6.69
|
0.01*
|
|
Visuospatial
|
116.16±24.63
|
115.50±19.69
|
0.12
|
0.90
|
103.24±22.59
|
116.21±6.92
|
3.90
|
0.01*
|
|
Processing speed
|
111.24±21.72
|
115.72±21.69
|
0.85
|
0.39
|
92.92±15.12
|
119.29±10.47
|
9.03
|
0.01*
|
|
Perceptual organization
|
98.04±24.03
|
100.76±18.95
|
0.52
|
0.59
|
89.12±16.14
|
111.67±8.98
|
8.01
|
0.01*
|
|
Planning and fine motor
|
110.00±10.41
|
112.34±12.04
|
0.84
|
0.40
|
105.80±20.07
|
120.00±12.08
|
3.92
|
0.01*
|
|
Verbal retention
|
103.55±16.47
|
102.63±8.58
|
0.33
|
0.74
|
92.10±11.44
|
98.61±4.94
|
3.36
|
0.01*
|
|
Motor speed (RH)
|
32.22±5.62
|
34.64±5.24
|
1.87
|
0.06
|
40.10±8.79
|
37.58±4.34
|
2.48
|
0.01*
|
|
Motor speed (LH)
|
27.06±5.55
|
28.87±5.54
|
1.35
|
0.18
|
33.48±6.76
|
33.74±6.00
|
0.17
|
0.86
|
|
Verbal learning
|
49.92±8.21
|
51.16±8.14
|
0.63
|
0.53
|
58.32±8.55
|
55.98±6.15
|
1.38
|
0.16
|
|
Verbal immediate memory
|
10.76±2.52
|
11.94±2.39
|
2.01
|
0.04*
|
11.64±1.97
|
13.20±1.26
|
4.25
|
0.01*
|
|
Verbal delayed memory
|
11.44±2.27
|
12.01±2.23
|
1.06
|
0.28
|
12.00±2.36
|
13.56±1.16
|
3.97
|
0.01*
|
|
Visual learning
|
69.20±11.78
|
70.27±13.80
|
0.33
|
0.73
|
74.24±7.49
|
76.52±12.74
|
0.83
|
0.40
|
|
Visual immediate memory
|
9.84±3.21
|
10.83±3.36
|
1.24
|
0.21
|
11.24±3.12
|
12.90±1.19
|
3.46
|
0.00**
|
|
Visual delayed memory
|
9.76±3.16
|
11.41±3.31
|
2.10
|
0.03*
|
11.72±3.00
|
12.56±0.87
|
1.92
|
0.10
|
|
Sustained attention#
|
91.20±36.72
|
82.34±36.37
|
1.00
|
0.31
|
77.56±24.77
|
69.58±24.02
|
1.36
|
0.17
|
|
Focused attention (CT-A)#
|
121.96±71.70
|
113.54±61.70
|
0.53
|
0.59
|
79.32±32.81
|
92.87±39.26
|
1.50
|
0.13
|
|
Focused attention (CT-B)#
|
240.08±137.42
|
235.70±120.12
|
0.14
|
0.88
|
160.68±71.88
|
131.29±39.19
|
2.36
|
0.02*
|
|
VW memory (NB 1)
|
8.28±0.97
|
8.47±0.74
|
0.97
|
0.33
|
8.16±1.34
|
8.83±0.37
|
3.47
|
0.01*
|
|
VW memory (NB 2)
|
10.48±2.48
|
11.36±1.82
|
1.78
|
0.07
|
10.20±1.84
|
12.85±1.40
|
7.07
|
0.01*
|
|
VSWM-F
|
4.24±0.83
|
4.29±0.80
|
0.25
|
0.79
|
4.64±0.70
|
3.52±1.10
|
4.62
|
0.01*
|
|
VSWM-B
|
2.56±1.66
|
2.69±1.69
|
0.32
|
0.74
|
2.56±1.50
|
3.52±1.10
|
3.23
|
0.01*
|
|
Verbal comprehension
|
31.86±5.05
|
33.15±4.38
|
1.15
|
0.25
|
32.02±3.53
|
35.34±0.798
|
6.66
|
0.01*
|
Neuroanatomical changes in children with acute lymphoblastic leukemia
Neuroanatomical changes were assessed using the results of MRI. The sample details
are summarized in [Table 6]. The baseline MRI of the eight children with ALL suspected to have neurotoxicity
showed no abnormalities in the brain. Of these, two children experienced neurotoxicity
during the intensive phase of treatment. Of the 25 children with ALL evaluated at
the maintenance phase, abnormalities on MRI were observed for three children: white
matter changes (best depicted in T2-weighted sequences) in periventricular deep white
matter regions extending to the centrum semiovale were noted in two patients (Grade
II) and in periventricular cortex in the left parietal region posteriorly (Grade I)
in one patient. The MRI (brain) images of the children with ALL who had changes are
shown in [Figure 3].
Table 6
Details of MRI (brain) with contrast of children with acute lymphoblastic leukemia
|
Variables
|
Baseline MRI
|
Post-MRI
|
|
MRI - Magnetic resonance image; SD - Standard deviation
|
|
Number of patients assessed, n
|
8
|
25
|
|
Male/female
|
4/4
|
16/9
|
|
Age (years), mean±SD
|
8.76±2.26
|
10.76±2.26
|
|
Time between diagnosis and
|
76.20±49.63
|
502.79±63.36
|
|
MRI (days), mean±SD
|
|
|
|
Changes observed in MRI, n (%)
|
-
|
3 (12)
|
Figure 3: Images of T2-weighted MRI (brain) for three children with acute lymphoblastic
leukemia who showed abnormalities. (a) Grade I: 13-year-old female. (b) Grade II:
8-year-old male. (c) Grade II: 6-year-old male
The white matter areas that were affected are associated with memory, executive functions,
and processing speed. Analysis of postassessment data of the three patients revealed
a reduced mean score for PIQ, working memory, visual immediate and delayed memory,
processing speed, verbal retention, visuospatial ability, attention, planning and
fine motor skills, and verbal comprehension, with further decrease in the fourth and
fifth assessments as compared to the baseline.
Discussion
This study assessed the neurocognitive functioning of children with ALL treated with
the BFM-95 protocol in comparison with that of healthy controls. The results showed
that the combination of CRT and IT-MTX along with HD-MTX as part of the modified BFM-95
protocol (CNS prophylaxis) affected the neurocognitive functioning of children with
ALL. Mild changes in neurocognitive functioning, following the intensive phase of
chemotherapy, were observed (IT-, HD-MTX); however, a significant effect was observed
with the addition of CRT. Children with ALL had poorer neurocognitive functioning
when compared to healthy children. Children with ALL who had MRI abnormalities performed
poorly on most of the neurocognitive tests. Significant effects in four specific domains
of neurocognitive functioning, namely PIQ, processing speed, visuospatial ability,
and verbal retention functioning, were observed.
We also evaluated PIQ using the Malin's Intelligence Scale for Indian Children (MISIC)
test. Across the five assessments, among children with ALL, PIQ significantly decreased
at the fourth and fifth assessments, as compared to the first, second, and third assessments
after receiving CNS prophylactic therapy along with HD-MTX.[17] Although a difference in the mean was noted, PIQ fell within the average range of
90–109 as per Wechsler IQ classification in all the five assessments for all the children
except two children with ALL (80–89).[15] The mean score was the highest at the second assessment. This could be explained
by the fact that the first assessment was performed immediately after the diagnosis
and during the induction period, when the child was coping with the diagnosis, the
new environment, and the treatment procedures. Both children with ALL and healthy
children performed similarly at the baseline, whereas children with ALL performed
significantly poorer in the postassessment. These results are consistent with the
findings of two previous Indian studies assessing the effect of CNS prophylaxis on
intellectual functioning of children with ALL. A study conducted by Jain et al. included 35 ALL children and 20 healthy children aged 5–15 years showed that children
with ALL performed significantly poorer in IQ tests when compared to the healthy children.
The difference in their mean scores was 13.6, where the children with ALL received
a CRT dosage of 20 Gy.[18] In this study, the mean PIQ score among ALL patients significantly decreased from
the first assessment to the fifth assessment (mean difference = 11.3). In their prospective
and longitudinal study, Abraham and Appaji reported that 19 children with ALL treated
with CNS prophylactic therapy in the age group of 6–12 years had a significant decline
in their IQ.[19] Another comparative Indian study conducted by Bhattacharya et al. revealed that the mean verbal intelligence quotient, PIQ, and full intelligence
quotient were comparable between the children who received CNS prophylactic treatment
and children with solid tumors who received chemotherapy alone, with the differences
not being statistically significant. However, the study reported that the dispersion
of IQ scores was greater in the children who received CNS prophylactic treatment with
a larger number of patients having scores of <80.[20] Similarly, in this study, only a few children had scores below the average (80–89)
across the five assessments, which indicated the difference in intellectual functions
between the different phases of treatment protocol. Furthermore, children with ALL
did not show significant differences in mean PIQ scores after undergoing the intensive
phase of chemotherapy (induction and consolidation phase). However, after the consolidation
phase, and CRT, a decline in the mean PIQ scores was observed. This finding is in
line with that of Brown et al. and Anderson et al. who did not find any immediate effect in the intellectual abilities of the children
with ALL treated with CNS-directed chemotherapy only.[21]
[22] Ochs et al. conducted a prospective longitudinal study with 43 children with ALL who received
CNS prophylactic treatment, and they observed significant deficits in IQ.[23] In line with these results, cross-sectional studies conducted by Anderson et al. showed that children receiving CRT and IT-MTX performed very poorly than those in
the nonirradiated groups on intellectual abilities.[22] However, CNS prophylactic therapy effects surfaced 1 year after diagnosis (mean
days = 510.23) in the present study. Similarly, a review study conducted by Copeland
concluded that neuropsychological impairments usually manifest within 1–3 years after
cranial irradiation and that deficits are progressive.[17]
[24]
On the MISIC subtests, when comparing the five assessments, we found that visuospatial
ability and processing speed of children with ALL significantly declined at the fourth
and fifth assessments when compared to the first and second assessments, after receiving
CNS prophylaxis along with HD-MTX. The results showed that the performance of children
with ALL was poorer in all five subtests of MISIC at postassessment, as compared with
healthy children: visuo-conceptual ability, visuospatial ability, processing speed,
perceptual organization, and planning. The performance scores of children with ALL
decreased from baseline to postassessment, and the scores of healthy children increased
from baseline to postassessment. These results, corroborated by those of many previous
studies, reveal that CNS prophylaxis is associated with decline in processing speed.[17]
[18]
[19]
[24]
[25]
[26] In addition to these functions, nonverbal functions such as visuo-conceptual ability,
planning and fine motor skills, and perceptual organization are also affected. Previous
reports indicate that children with ALL treated with CNS prophylactic treatment tend
to show impairments, as documented by Anderson et al.[17]
[18]
[21]
In this study, verbal learning, memory, and retention were assessed using the Rey
Auditory Verbal Learning and Memory Test (RAVLT). Using RAVLT, we found that verbal
retention declined from baseline to postassessment in children with ALL who had received
CNS prophylaxis therapy along with HD-MTX. This decline in verbal retention was progressive
after the commencement of treatment. It is possible that both CRT and chemotherapy
affected performance in this domain. This finding was in accordance with that of Précourt
et al. and Krull et al. who attributed the decline to IT-MTX and CRT.[27]
[28]
Furthermore, other neurocognitive functions such as motor speed (right and left hand),
attention (sustained and focused attention), learning and memory (immediate, delayed,
and retention for visual and verbal), visuospatial ability and verbal working memory,
and verbal comprehension were not significantly affected in this study. Of interest,
improvements were observed in motor speed, focused attention, verbal and visual learning,
and visual immediate memory across the five assessments. Similar findings were noted
in a previous study, with no significant decline in motor speed,[29] attention,[30]
[31] verbal and visual learning, visual memory,[32] visuospatial working memory,[29]
[30] verbal comprehension,[32] verbal short-term memory,[30] and verbal memory and visual memory.[32]
In this study, compared with the healthy children, the children with ALL had significantly
poorer neurocognitive functions such as PIQ, visuo-conceptual ability, visuospatial
ability, processing speed, perceptual organization, planning and fine motor skills,
verbal comprehension, verbal working memory, visuospatial working memory, verbal immediate
memory, verbal delayed memory, and visual immediate memory. In line with these results,
Giralt et al. reported significant differences between patients with ALL and controls in all domains
of neurocognitive functions.[33] Another report described that children with ALL treated with cranial irradiation
experienced problems in cognitive and educational abilities compared with healthy
controls or children treated with chemotherapy alone.[21]
[34]
Neuroanatomical deficits, common among childhood ALL survivors, include white matter
abnormalities, which may result from the disruption of the myelinization process occurring
during childhood because of HD-MTX, which is worsened by whole-brain irradiation.
Microangiopathy has also been reported in associated with this treatment. MRI scans
performed in this study also revealed abnormalities in brain structure for three children
with ALL, and these children had poor performance in PIQ, working memory, visual immediate
and delayed memory, processing speed, verbal retention, visuospatial ability, attention,
planning and fine motor skills, and verbal comprehension.[35]
[36]
[37]
[38]
[39] This could be because of white matter changes in the brain.
Although deficits in few of the neurocognitive domains were observed in children with
ALL treated with the BFM-95 protocol and the scores were poorer in many of the domains
as compared to those of the healthy controls, these deficits could also be because
of several other factors. For instance, these patients missed long durations of regular
schooling, an academic, environment, and intellectual stimulation during their treatment.
We observed that parents of most patients were overprotective; this might have limited
the patient's learning opportunities. Further investigation is needed to understand
the effect of these aspects on neurocognitive functioning of children with ALL. Long-term
investigation or regular follow-up of children with ALL after they resume schooling
and comparing their academic performance will provide insight into whether these functions
can be resumed to normal (before treatment) over a longer period of time or if the
changes are permanent and progressive.
Conclusion
The study results show that treatment with the BFM-95 protocol, which includes CNS
prophylaxis along with HD-MTX, affects neurocognitive functions in children with ALL.
This protocol had impacted neurocognitive domains such as performance intelligence,
processing speed, visuospatial functions, and verbal retention. However, children
with ALL had poorer neurocognitive functioning when compared to healthy children.
These findings highlight the need for effective, less toxic treatment for patients
with ALL and cognitive retraining for patients receiving CNS prophylaxis.
