Neuro-Cognitive Functions in ALL Childhood Cancer Survivors in NCI, Cairo University, Egypt ()
1. Introduction
Acute Lymphoblastic Leukaemia (ALL) is one of the most common childhood malignancies, accounting for about a quarter of all childhood malegnancies, with a peak incidence at the age of 3 - 4 years [1].
Current treatment commonly lasts for 24 - 30 months. Almost entirely all protocols include central nervous system prophylactic treatment to prevent relapse. Treatment is based mostly on complex multi-agent combinations of chemotherapies; the intensity of the therapy is determined according to risk groups, defined by graded risk for relapse and long-term sequel. Some very high-risk cases also involve the use of cranial radiation therapy (CRT) [2].
Central nervous system (CNS)-directed therapy is an integral part of ALL treatment. Prophylactic CNS-directed radiotherapy has been mostly abandoned due to its detrimental effects on brain development and intellectual functioning. In more current treatment protocols, intensified CNS-directed chemotherapy, with intravenous (IV) and intrathecal (IT) methotrexate (MTX) as major backbones, has replaced radiotherapy [3].
However, chemotherapy-based CNS-directed treatment may have a negative impact on cognitive functioning in ALL survivors as well, although likely to a lesser extent than radiotherapy [3].
Earlier studies that focused on treatment effects often reported fewer and only subtle deficits in the chemotherapy only groups as compared to survivors treated with CRT, while other studies have reported no significant cognitive differences between such groups [2].
Studies that have focused on both treatment and illness factors by including multiple samples (CRT treatment, chemotherapy only treatment, other illnesses such as non-central nervous system cancer and healthy controls) have shown a gradual effect on cognitive functions [2].
Recent research has concentrated on more specific cognitive abilities and ALL survivors have been reported to show deficits in several neuro-cognitive domains, such as processing speed, attention, executive functions, and working memory [3].
The lower scores on the Wechsler Intelligence Scale for Children as documented in the literature might reflect impairment of both global and/or specific neuro-cognitive abilities. In fact studies that focused on outcomes for specific cognitive functions have reported significant impairment in Verbal IQ, Performance IQ, attention, information processing, executive functions, psychomotor skills, as well as verbal visual memory [4] and learning difficulties. Specific impairment in non-verbal function and freedom from distractibility has been documented, but specific impairment of Verbal IQ has also been documented [1].
As brain development continues into early adulthood, long-term cognitive outcomes in ALL survivors may not become evident until years after completion of treatment. Until now, follow-up time in ALL survivors treated exclusively with chemotherapy has been limited, and thus, little is known about long-term neurocognitive functioning in ALL survivors who have lived for more than 10 years after their diagnosis [3].
The objective of this study was to evaluate cognitive consequences in childhood Acute Lymphoblastic Leukemia survivors at national cancer institute, Cairo University treated with chemotherapy and to evaluate correlation between cognitive functions and different variables such as: demographic, protocol given, duration of therapy, etc.
Statistical Analysis
Statistical analysis was done using IBM SPSS® Statistics version 22 [5] Numerical data were expressed as mean and standard deviation or median and range as appropriate. Qualitative data were expressed as frequency and percentage. Pearson’s Chi-square test was used to examine the relation between qualitative variables. All tests were two-tailed. A p-value < 0.05 was considered significant.
Sample size was calculated using G * Power program (University of Düsseldorf, Düsseldorf, Germany).
2. Methods
The present study consists of 61 children long-term survivors of childhood ALL and 34 healthy controls matched for age, gender and socio-demographic variables.
The children in the ALL survivor group were recruited from Pediatric Oncology Department, National Cancer Institute, Cairo University; evaluated and assessed in collaboration with the Psychiatry Department, Faculty of Medicine, Cairo University during the period of 6 months started in January, 2019.
ALL survivors initially diagnosed between 2008 and 2013, completed their treatment according to total XV protocol and were under follow up at least for 2 years.
Patients included in the study if they are confirmed acute lymphoblastic leukemia patients who ended treatment according to T XV protocol [6].
Age: 6 - 12 years old at study entry ≥ 2 years off treatment in continuous first remission (1st CCR), written informed consent from the parents or caregiver, any risk group.
Patients were excluded in case of relapse; patients received cranial or cranio-spinal irradiation, patients who underwent Bone Marrow transplantation, patients having Down syndrome or any other syndrome causing mental disability or showing psychiatric symptoms on CBCL [7].
Data of eligible patients were collected from medical records as sociodemographic data as age, sex..., etc., data at presentation including clinical picture, signs and symptoms, WBC count, CSF cytology, brain imaging studies and other organ function tests. Protocol and chemotherapy agent received according to total XV protocol, response to therapy.
Semi structured interview with every study patients’ caregiver was sustained to assess: developmental history whereas the caregiver is interviewed about the developmental milestones, any co-morbidities or chronic illness or psychiatric disorder, previous history of school performance.
Cognitive assessment was tested using the Wechsler Intelligence Scale for Children (WISC) (for age range 6 - 12 years) [8]. The WISC is a collection of 13 distinct subtests divided into two scales―a Verbal Scale and a Performance Scale. The six Verbal Scale tests use language-based items, whereas the seven Performance Scales use visual-motor items that are less dependent on language. The test was administrated by a clinical psychologist from Cairo University. The duration of the test range between 45 - 50 min per each case. Once a child’s performance on a subtest is compared to the normative sample, subtest scores were converted into scaled scores that serve as one of the universal metrics for this test.
Child Behavior Checklist (CBCL) developed by Achenbach 6 for completion by parents. The scale consists of 113 questions to which the parents had to circle the 2 if the item is very true or often true of their child's behavior now or within the past six months; to circle the 1 if the item is somewhat or sometimes true and to circle the 0 if it is not true of their child. The total score could be obtained by summation of the scores of each statement, so it ranged between 0 and 224. The CBCL also contains different subscales showing the type of the problem namely: depressed, somatic complaints, social withdrawal, delinquent, aggressive and hyperactive.
All the human experiments were conducted with ethical standard and after written consent from the caregivers.
3. Results
61 children long-term survivors of childhood ALL and 34 healthy controls, 65.6% were males (Table 1). WISC III total scores showed significant difference between ALL survivors group and control group, control group showed higher values than ALL survivor group 98.7 ± 10.3 vs. 84.8 ± 10.0 respectively with p-value < 0.001.
Results showed significant difference in both verbal and performance IQ results between both groups, control group showed higher values than ALL survivors group with significant p-value < 0.001. This indicates that there is significant difference between the two groups regarding the cognitive functions (Table 2). When the two groups were compared to the normal ranges of the IQ there was significant difference as regard the total IQ scores with p-value < 0.001 in front of control group (Figure 1).
There was significant difference between the two groups in the subscales of
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Table 1. Socio-demographic characteristics and treatment variables in survivors and control.
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Table 2. WISC III results between ALL survivors and control group.
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Figure 1. Percentage of results of IQ in each group.
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Table 3. Relation between IQ Results and Gender
the Verbal IQ with significant p-value. It indicated that the control group had better memory, social knowledge, logic thinking and attention (Table 2).
There was significant difference between the two groups in the subscales of the Performance IQ except for the picture arrangement subscale with significant p-value. It indicated that the control group had better perception, language, coordination and concentration (Table 2).
The study patients were followed up from 2 to 7 years with mean duration of 5 years. The number of survivors who completed three years follow up were 29 (47.5%) compared to 32 (52.4%) who were more than three years follow up. There was no significant difference in the cognitive affection between the two groups as regard Total, Verbal and Performance IQ.
There was significant difference between the two subsets regarding the Verbal IQ with p-value 0.045 with higher verbal IQ among males. The total WISC III score showed slight difference between males and females with insignificant p-value 0.083 (Table 3).
This showed that male survivors have better cognitive functions regarding memory, attention, logic thinking and social knowledge. There was no significant difference between the two subsets regarding the Performance IQ (p-value 0.681) with no difference in language, perception, co-ordination and concentration.
The study included 39 patient 64% with low risk disease and 22 patient 36% with standard risk disease, there was no significant difference between the two groups regarding cognitive affection despite the difference in intensity of chemotherapy received.
4. Discussion
The present study indicated that children treated for ALL early in life by che-motherapy only showed decreased global neuro-cognitive functioning. Their achievements on Total IQ, Verbal IQ and Performance IQ, were all below the matched control group with (84.8 ± 10 vs. 98.7 ± 10.3), (94.4 ± 13.5 vs. 110.1 ± 13.6) and (76.6 ± 10 vs. 85.5 ± 8.5) respectively with statistically significant difference (p-value 0.001). Group comparisons of the profiles from the WISC-III subtests scores indicated decreased level in verbal functioning, complex problem solving for arithmetic tasks, attention and memory.
This agreed with results of Lofstad that stated group differences of specific cognitive functions was most striking and consistent for verbal function (Verbal IQ) and attention (Freedom from Distractibility Index) [2].
Data from Lofstad study indicated deficits in complex visual spatial problem solving as measured by Block Design (9.6 ± 3.0 vs. 11.7 ± 2.4) with p value 0.002 and Object Assembly (9.7 ± 3.9 vs. 11.3 ± 2.1) with p value 0.028, but not in the less abstract Picture Completion (9.9 ± 3.1 vs. 9.6 ± 2.8) with p value 0.747 and Picture Assembly (10.3 ± 3.2 vs. 11.5 ± 2.9) with p value 0.119 subtests, which load highly for detail recognition.
The ALL survivors in this study did not differ significantly from controls for long memory of learned facts, recognition and field-dependent visual tasks [2].
Khalifa et al. also found that the most pronounced effects on cognitive functions were observed in the survivors group who showed significantly lower verbal, performance and total IQ compared to controls [9]. They also stated that Survivors treated with modified CCG protocol showed a significant decrease in all cognitive tests compared to control (p < 0.05) [9].
As reported by khalifa et al. [9] comparison of different patient subgroups regarding verbal IQ (VIQ), performance IQ (PIQ) and total IQ (TIQ) was not significant except for survivor group who showed significant reduction of the VIQ (p < 0.01).
Survival patients showed significant reduction in arithmetic ability as well as in similarity subsets (p < 0.01). Specific decreases in verbal functions have been documented previously by Kingma et al. [10] The ALL survivors in their study performed significantly below a large Dutch normative group on Verbal IQ, but no other scores showed significant differences.
Among several studies reported over the last decade [4] [11] [12] a lower group mean total IQ in ALL survivors of 8.3 to 22.2 IQ points compared to a matched healthy controls in contrast to Kaemingk [13] who reported no major cognitive impairment in ALL survivors using chemotherapy only.
Documentation of delayed brain changes, most commonly in reduction in the white matter volume, calcification, changes in glucose utilization and abnormalities in event related potential (ERP), strengthen the hypothesis of decreased levels in cognitive functioning [2].
The present study showed slight significant difference between males and fe-males regarding total IQ scores (86.5 ± 10.2 vs. 81.5 ± 9.1) with p-value 0.083 and the Verbal IQ scores (96.6 ± 14.3 vs. 90.1 ± 10.9) with p-value 0.045. Males showed better cognitive functions compared to females in the ALL survivors’ group.
These results are in agreement with Sherief [14] that sex plays an important risk factor for deterioration of neuro-cognitive function in survivors of ALL treated with chemotherapy alone as there is significant differences in both verbal and performance IQ scores between girls and boys, with girls do worse than boys in all IQ parameters except in vocabulary and picture arrangement subtests.
This was stated in review of literature that several studies found differences in performance between girls and boys, with girls consequently performing more poorly than boys. There is no definite explanation for this disparity. It has been hypothesized that gender differences in brain maturation may underlie varying vulnerabilities between girls and boys. Increase in white matter during childhood has been demonstrated to be smaller in girls than in boys, which could make girls more vulnerable to neurotoxic effects of chemotherapy [15].
Jacola [16] also reported that females may be at increased vulnerability because of sex-based differences in white matter development, including greater increase and later peak volume in healthy males.
In another study it was found that females continued to be at greater risk for impulsivity and hyperactivity. These findings are consistent with existing research that identifies female sex as a risk factor; however, in the study they did not identify an appreciable impact of sex on neuro-cognitive ability at the end of therapy [17].
In our study the effect of intensified chemotherapy and age at diagnosis were studied in relation to their effect on cognition function, it showed no significant effects within the study ALL children.
However, in Jacola study their results suggest that treatment with higher-intensity CNS directed chemotherapy and younger age at diagnosis continue to confer increased risk for neurocognitive difficulties 2 years after therapy [16].
Also Sherief et al. [14] stated that young age of onset of chemotherapy appears to be more risky for developing cognitive dysfunction as there is significant difference in comparison patients whose age of onset of the disease below than those above 5 years old in Wechsler performance IQ scores (except in picture completion & mazes, there is no significant difference), at the same time there is no significant difference in Wechsler verbal IQ scores. In consistence with literature, young age at diagnosis was demonstrated to be a risk factor for cognitive dysfunction in children with ALL treated with chemotherapy only in a substantial number of studies.
It has by now been widely accepted that children younger than 5 years of age at diagnosis of ALL are more susceptible to long-term sequelae of treatment. It is becoming apparent that this applies not only to cranial irradiation, but also to CNS-directed chemotherapy [18].
In our study the effect of duration of follow up from end of treatment was studied on the cognition functions in ALL survivors, we studied after two years follow up and three years follow up after end of treatment with 29 survivors who completed three years follow up compared to 32 who were more than three years follow up.
It showed no significant relation to affection of cognition function, increase or decrease of the duration does not affect the degree of cognition affection with p-value for total IQ scores 0.750.
It might be more reasonable to follow those patients for longer periods of time aiming at eliciting any potential difference with time.
This agrees with khalifa et al. [9] which stated that there was no significant correlation between chemotherapy duration and VIQ, PIQ, and TIQ in all groups (group IV survivors for two years or more).
On contrary Campbell reported that length of time since treatment was not found to consistently moderate the significant effects and therefore the extent to which it influences the findings remains unclear [19].
Krull also reported the increased risk for executive function impairments with increased time since diagnosis [20].
This pattern may result from several processes. First, executive functions develop throughout adolescence and well into adulthood, and early injury may alter the trajectory of development such that skills lag farther behind with passing years. In addition, survivors are at increasing risk for chronic health conditions as they age, and health conditions can have an impact on executive function. In this regard, time since diagnosis was also associated with increased risk for self-reported behavioral problems.
5. Conclusion
The present data strongly supports the hypothesis that early childhood ALL treated by chemotherapy only influences subsequent brain development and is followed by cognitive sequels as evidenced by Alias et al. [21], Liu et al. [22], Zając-Spychała et al. [23]. Females are more likely to have neuro-cognitive affection among survivors of childhood ALL treated with chemotherapy-only protocols. Age at diagnosis and risk stratification did not show significant differences between different groups. Therefore, further reduction of neurotoxic medications and less chemotherapy administration to ALL patients has to be always attempted in further protocols keeping the same or better survival rates.
Acknowledgements
Thanks to the patients and their family for contribution in the questionnaire. Thanks to the supervising professors for making this work sees the light.
Appendix 1―List of Abbreviations
Abbreviation Stands For
ALL Acute Lymphoblastic Leukemia;
AML Acute Myeloid Leukemia;
aPTT Activated Partial Thromboplastin Time;
BASC Behavior Assessment System for Children;
BRT Brain radiation treatment;
BT Brain tumors;
CBCL Child behavior check list;
CDI Children Depression Inventory;
CNS Central Nervous System;
COG Children Oncology Group;
CR Complete remission;
CRT Cranial Radiation Therapy;
CSF Cerebrospinal fluid;
CT Computed Tomography;
CU Cairo University;
EEG Electroencephalography;
EF Executive functioning;
EFS Event-free survival;
ETP Early T-precursor;
FAB French-American-British;
fMRI Functional Magnetic Resonance Imaging;
GWAS Genome-wide Association Studies;
HR High risk;
ICD International Classification of Disease;
IDDM Insulin-dependent diabetes mellitus;
IQ Intelligence Quotient;
IRB Institutional review board;
LR Low risk;
MEG Magnetoencephalography;
MLL Mixed-Lineage Leukemia;
MRD Minimal residual disease;
NCI National Cancer Institute;
NOS Not Otherwise Specified;
PCR Polymerase chain reaction;
PIQ Performance IQ;
PT Prothrombin Time;
PTSD Post-traumatic stress disorder;
QOL Quality of life;
RCMAS Revised Children’s Manifest Anxiety Scale;
RPM Raven’s Progressive Matrices;
SAI School Ability Index;
SCD Sickle cell disease;
SCT Stem cell transplantation;
SDQ Strengths and Difficulties Questionnaire;
SJCRH St Jude Children’s Research Hospital;
SR Standard risk;
TIQ Total IQ;
TLP Traumatic lumbar puncture;
TPMT Thiopurine methyltransferase;
VIQ Verbal IQ;
WBC White blood cells;
WHO World Health Organization;
WISC Wechsler Intelligence Scale for Children.