Discussion
Our study demonstrated that pediatric HCT survivors reported higher
impairments in specific CCSS-NCQ neurocognitive domains of emotional
regulation, task efficiency, memory, and organization but average
cognitive quality of life compared with general population norms at a
median of 27 years post-transplant. Despite reported problems with
specific cognitive abilities, reassuringly these problems were not
perceived to have significant consequences on daily life as reflected on
the Neuro-QoL. This could represent adaption to cognitive difficulties
over time or an adjustment in expectations. These results reflect the
long-term follow-up period of our patient population, in contrast with a
shorter-term study in pediatric HCT survivors that described largely
stable intelligence and academic achievement through 5 years
post-HCT.12 Given the limited studies of late
neurocognitive effects among pediatric HCT survivors, some comparisons
can be drawn from CCSS studies of childhood cancer survivors at a
similar follow-up interval.4,9,25 In a report from the
CCSS featuring over 6,000 survivors (mean age 32 years), a lower
percentage (12.5-22.4%) reported impairments in the CCSS-NCQ
domains.9 Although not directly comparable, this
suggests that pediatric HCT survivors may be more likely to report
neurocognitive impairments compared with general pediatric cancer
survivors.
Various treatment characteristics and exposures have been explored in
terms of their association with neurocognitive dysfunction. Previous
literature has suggested that younger age at time of cancer diagnosis or
HCT is a risk factor for worse neurocognitive
function.4,14,15 While a cohort study of pediatric HCT
survivors initially demonstrated overall stability in cognitive
functioning at 5 years post-HCT,12 a follow-up study
with an expanded cohort showed that patients <3 years at time
of transplant may be particularly susceptible to the cognitive impact of
TBI, with lower IQ (16 points on average) at 5 years post-HCT compared
with those who did not receive TBI.26 In our study,
younger age <10 years at time of HCT was suggestive of worse
outcomes after multivariable analysis, although the study may have been
underpowered to detect a statistically significant association.
Additionally, the sample size was too small to draw any conclusions in
the cohort <3 years at time of HCT. As above, radiation
exposures such as TBI and cranial irradiation have been associated with
neurocognitive dysfunction.3,11 While we did not find
a difference between non-irradiated survivors versus those who underwent
TBI only, those who received pre-HCT cranial irradiation were more
likely to report worse neurocognitive function. In our cohort, survivors
treated with cranial irradiation reported impairments in the CCSS-NCQ
domains comparable to childhood CNS tumor
survivors,8,27,28 as well as pediatric ALL survivors
treated with cranial irradiation, with significant late cognitive
deficits detected at a median follow-up of 28.5 years after
treatment.29
Subsets of pediatric HCT survivors were more likely to have impaired
neurocognitive function, including those with hearing conditions
(moderate to severe hearing loss or more bothersome tinnitus), history
of stroke or seizures, or sleep disturbances. The association of poor
long-term neurocognitive outcomes in survivors with a higher burden of
chronic health conditions is unsurprising, given previous
studies.25 Specifically for long-term pediatric cancer
survivors, hearing and visual deficits have been associated with
impaired emotional regulation and organization,4 while
history of stroke is associated with worse health-related quality of
life and neurocognitive function, particularly task efficiency and
memory.30 Lastly, we found that self-reported sleep
disturbances were significantly associated with greater impairments in
all CCSS-NCQ domains and worse cognitive quality of life. Given the
cross-sectional nature of our study, we were unable to determine if
sleep issues had a causal effect on neurocognitive function. However,
pediatric cancer survivors who reported greater fatigue and poorer sleep
quality have also exhibited greater impairments in all CCSS-NCQ
domains.31 Studies of pediatric cancer survivors have
reported a greater burden of sleep disturbances and fatigue compared
with non-cancer controls.6,32 Additional research to
better characterize the sleep disorders experienced by our patients may
help determine specific targets for intervention.
For pediatric HCT survivors over the age of 25 years at the time of
survey completion, greater impairments in all CCSS-NCQ domains and worse
Neuro-QoL scores were associated with less educational achievement
(defined as less than college education). Our findings are similar to
other studies showing that childhood cancer survivors with
neurocognitive deficits are less likely to attain educational
milestones, obtain employment, or live
independently.3,4 These results may be time-dependent,
as differences in educational achievement may not be fully appreciated
until an extended time interval after HCT. This highlights the
importance of early referrals for resources or interventions to
potentially mitigate HCT treatment effects. The Children’s Oncology
Group’s Long-Term Follow-Up guidelines recommends routine formal
neuropsychological evaluation for patients at risk for late
neurocognitive deficits, including those who receive any cranial
irradiation (including TBI) or specific chemotherapy agents commonly
used during HCT, including intrathecal methotrexate, high-dose
intravenous methotrexate and/or cytarabine.33 While
previous pediatric HCT reviews3,15 have suggested the
implementation of similar routine screening, further studies will be
needed to study if earlier testing and intervention improves long-term
outcomes.
Our study benefited from a very long average follow-up duration, greatly
exceeding that of other studies of neurocognitive outcomes among
pediatric HCT survivors. Additionally, our study also featured one of
the largest samples examining neurocognitive outcomes in this patient
population. However, there were several limitations to this study. Our
study was conducted at a single center and limited by lower response
rate; thus, our results may not be fully representative of the overall
population of pediatric HCT survivors. Non-responders were more likely
to be younger and male; however, when inverse probability weighting was
applied to represent the entire cohort, we did not find a meaningful
difference in our results. It is unclear how potential response bias
would have influenced these results, as those with lower function or
quality of life may have been both less likely to respond or possibly
more likely to participate given the nature of the survey. Lastly, while
our study was based on self-reported measures with no objective
neurocognitive testing, many components of cognition can only be
captured by patient self-report and we relied on well-validated surveys
which enabled comparisons with the general population.