DISCUSSION
One of the main challenges after curative treatment of childhood cancer
is maintaining an effective follow up to assess various health related
complications. There are a wide range of late effects as a result of
cancer and its therapeutic exposure. Studies have shown that the
cumulative number of health conditions in survivors of ALL are actually
twice that identified among matched controls, particulary
cardiovascular, endocrine, reproductive and neurological
sequelae10. At a mean duration of around 5 years from
diagnosis, 50% of our cohort of ALL survivors showed significant
disturbance in neurocognitive function. Around 75% of our cohort showed
a deficit in atleast one domain of neurocognition, which includes verbal
comprehension, working memory, processing speed and perceptual
reasoning. This is comparable to a large series of adult survivors of
ALL, where neurocognitive impairment ranged between 28.6% for
self-reported behavior problems to 58.9% for direct assessment of
executive function4. The mean FSIQ of ALL survivors
from developed countries are almost 20-30 points higher than in our
cohort11,12. This could be due to regional variation
in IQ and socioeconomic status between the two cohorts. However it also
signifies the greater need to implement more stringent long term follow
up guidelines in LMICs as the baseline prevalence of neurocognitive
impairment is high.
Data on neurocognitive outcome in survivors of ALL in LMICs is scarce.
According to a review of neurocognitive impairment in Asian Cancer
survivors, mild-to-moderate impairment was reported in 10.0–42.8% of
survivors13. A large series of cancer survivors from
India, showed scholastic problems and psychosocial problems in around
43% and 57% of the cohort, respectively14. Racial,
regional and ethnic variations of cancer and its treatment are known,
which increases the burden of chronic health condition in this growing
survivor population in LMICs. Hence, the importance of country specific
databases of childhood cancer survivors.
As early as 1988, neurobehavioural effect of CRT in survivors of ALL
have been demonstrated15. These late effects include
deficits in attention, memory, processing speed, and visual spatial
skills16. Demyelination with loss of white matter,
microvascular damage, loss of neuronal precursors in hippocampus, basal
ganglia and thalamus are all proposed mechanisms for long term radiation
induced cognitive decline17. This neurocognitive
morbidity in survivors of childhood ALL has led to the phasing out of
radiation, almost completely from the management of
ALL18,19. Acute changes in the brain occurring during
chemotherapy are also associated with long term neuro behavioural
problems20. Despite elimination of CRT, modern
treatment protocols including high dose methotrexate and IT
methotrexate, have been implicated in long term problems in memory,
executive function, attention and processing
speed4,21,22. Methotrexate depletes the folate pool
which in turn depletes the availability of methyl-groups and produces an
excess of homocysteine and alternative one-carbon sources such as
choline and betaine. This leads to an impairment in myelin formation and
stabilisation and is a likely explanation for methotrexate induced long
lasting neurodevelopmental impairment23. Higher plasma
methotrexate levels have been shown to be associated with poorer
executive function scores4. In one study methotrexate
decreased the processing speed by 3% for each 1g/m2of methotrexate4. A study comparing IT methotrexate
with triple IT revealed minor reduction in processing speed in survivors
of ALL. CRT, high dose methotrexate and IT therapy have a neurotoxic
effect in the early course of therapy. As time passes neurocognitive
problems are a result of other therapies like glucocorticoids. The
cerebellum and hippocampi have higher number of glucocorticoid receptors
and are more affected by exposure to prolonged and high doses of
steroids24. Comparisons between different
glucocorticoids have also been made. Neurocognitive outcome measures
evaluated in survivors receiving dexamethasone or prednisolone during
induction of ALL, found no difference in outcome measures in either
group25. Even though almost half of our cohort had
neurocognitive dysfunction, the scores were not different in groups of
patients receiveing higher dose of CRT compared to lower doses(24Gy vs
18Gy). Higher dose of methotrexate or use of IT methotrexate so did not
appear to have adverse effect on neurocognition in our group of
survivors. Other factors that can be evaluated to assess the risk of
neurotoxicity include markers of oxidative stress26,
cytokines like tumor necrosis factor(TNF) alpha and
interleukins27 and cerebrospinal fluid
biomarkers28.
Neurocognitive dysfunction is seen to be more significant as age
increases29. Attention problems detected at the end of
therapy in survivors of ALL predicted decreased academic performance 2
years later, especially in females and children who had a younger age at
diagnosis30. It is also believed that patients
diagnosed at a younger age and those who received CRT, perform poorly in
neurocognitive domains13,16. A younger age at
diagnosis correlated with poor working memory scores in our cohort.
Other domains were not affected by either the age at diagnosis or
assessment. Nevertheless, assessment of neurocognition in survivors of
ALL should start at a younger age, especially in children in LMICs,
where focus is more on survival than survivorship, to allow them to
reach their full potential at school and in the workplace.
Additional factors which put a survivor at increased risk of
neurocognitive impairment, like polymorphisms in genes related to
neurodevelopment, genes affecting the folate pathway and genes that
regulate oxidative stress, have been studied31. This
can not only help us in stratifying patients according to their genetic
risk but also help in tailoring treatment and prophylaxis early in
development32. Since regional variations affect the
genetic makeup of an individual, country specific multicentre
collaborative studies are in much need.
There is limited research examining how a childs neurocognitive function
following treatment for cancer is associated with parenting factors. A
recent study reported that parents respond to child executive function
difficulties with greater over protection. Greater years of maternal
education were related to less parental perceptions of child
vulnerability and less over protection33. A univariate
analysis in our cohort, showed a significantly lower Intelligence
quotient(IQ) in survivors whos’ parents had fewer years of education.
Other factors like lower socioeconomic status and increased birth order
are also associated with lower IQ scores. These are predictable and
understandable findings and may also be seen in children who are not
cancer survivors. However, since other factors including radiation dose,
intensity of chemotherapy or age at primary diagnosis did not alter
outcome, focus of neurocognitive behavioural assessment and intervention
should be more focussed towards this more vulnerable group of children
and adolescents to mitigate the impact of therapy on neurocognitive
outcomes.
Poor neurocognition in ALL survivors, has been associated with a marked
decrease in quality of life due to increased chronic health
morbidities34. Survivors of ALL have been believed to
perform poorly in school because of probable dysfunction in executive
function abilities(4(p20). Compared to their siblings,
they have greater degrees of inattention-hyperactivity, anxiety,
depression, social withdrawal and learning problems. Adolescent
survivors with neurocognitive impairment are also less likely to
graduate from college than survivors without any
impairment30. The St Judes Lifetime Cohort study
concluded that though survivors of ALL had significant neurocognitive
impairment, overall their educational attainment and employment status
was similar to controls4. Delay in schooling is a
major concern in survivors of ALL from India. Our cohort showed an
average of 27 months of delay in schooling despite our best efforts.
LMICs, which have their own cohort of young survivors, with poorer
overall exposure to basic education, must focus on routine longitudinal
screening in childhood survivors of ALL, optimizing their educational,
vocational, and social outcomes based on local, regional and cultural
practices.
Following a good assessment, survivors of ALL with neurocognitive
impairment, should should be taught deficit specific compensatory
interventions. This may be a computerised, home, school or even
community based training31. Pharmacological agents
have also been studied. Methylphenidate resulted in a statistically
significant improvement in measures related to
attention35. Future research should focus on
interventions to improve neurocognition in ALL survivors.
Several limitations should be considered in interpretation of these
results. Firstly, this was a cross sectional study with a small sample
size restricted by geographical coverage. Secondly baseline
neurocognitive functions of these ALL survivors were not known and there
was no healthy control group for comparison. Assessment at time of
initiation of treatment may have yieldied falsely low scores associated
with anxiety and stress at diagnosis. Thirdly, due to a lack of region
specific assessment tools for neurocognitive function, we had to use
region specific adaptations of the assessment tool which allowed certain
substitutions. Limitations notwithstanding, comparisons were made across
treatment groups and patients with or without significant neurocognitive
impairment. In addition, the primary focus of this study was to assess
the neurocognitive impairment in a group of survivors from a LMIC where
baseline educational and vocational opportuinites are challenging even
for children without cancer. To the best of our knowledge this was the
first study in India, a LMIC, in which WISC-IV scale was used for the
assessment of neurocognitive functions in the survivors of childhood
ALL. We looked extensively into various factors associated with
neurocognitive deficits including host, disease and treatment related
factors.
In conclusion, data on neurocognitive outcomes in survivors of ALL are
extremely scarce, this being particularly true for our country. Ethnic,
geographic and genetic variations predispose survivors differently to
adverse chronic neurological toxicities. This can explain the difference
in prevalence, severity, and presentation of neurocognitive impairment
in survivors of ALL in LMICs. More data from LMICs are needed to assess
the time to initiate screening and ways to identify potentially
remediable risk factors which in turn will enable us to develop
culturally appropriate preventive and rehabilitative interventions.