FIGURE 1 Flow diagram showing the selection procedure
Results
3.1 Study Characteristics
A total of 2 232 unique articles were identified from the search of
which 27 were included upon full text screening (Figure 1). One
additional paper was included based on manual reference tracking.
Cohen’s K=0.94 for interrater reliability.
The characteristics of the 28 included articles are presented in Table
1. Nineteen unique study populations were identified among all included
articles. Studies were conducted in North America (USA: n=20, Canada:
n=4), Europe (n=3), or Australia (n=1), and published between 2001 and
2022. Only 12 studies exclusively included patients with a PBT.
Participants’ mean age at diagnosis and at study inclusion ranged from
3.5 to 10.0 years and 10.3 to 19.8 years, respectively. Most studies
recruited patients who completed cancer treatment, while two studies
included patients during their cancer therapy, and one study included
both13–15. Furthermore, fifteen articles implemented
the inclusion criterion of NCI in at least one
domain16–30 .
The effectiveness of the interventions was measured in nearly all
studies using objective neurocognitive assessments, or proxy-reported
measurements of neurocognition (Table 2). Almost half (n=13) of the
articles measured intervention efficacy immediately post-intervention
(less than 3 weeks after intervention or indicated as
post-intervention)19–25,30–35. The other half (n=15)
also considered and measured maintenance of possible intervention
effects (range 12 weeks – 2.9 years after intervention
completion)13–18,26–29,36–40. For results of risk
of bias, we refer to supplementary information (Supplementary Figure
S1).
3.2 Types of interventions for
NCI
Three categories of interventions were distinguished: 1) lifestyle
interventions, 2) cognitive training, and 3) pharmacological
interventions. An overview of different interventions and their results
are given in table 1 and 2.
Lifestyle interventions
Four articles (3 study populations) implemented a 12-week aerobic
exercise training program 13,33–35. Immediate
improvement in reaction times was seen when participants trained in a
group setting, and these improvements could be predicted by improved
fitness33,35. Furthermore, exercise training showed a
positive impact on white matter microstructure (as indicated by higher
fractional anisotropy based on diffusion-weighted MRI) as well as
hippocampal volume, and on MEG-derived functional connectivity. The
positive effect on white matter microstructure maintained at 12 weeks
after completion of the training. Additionally, the training program led
to an increase in cortical thickness which was also associated to a
decrease in reaction time35. One study reported that
no adverse events occurred, and that drop-out rate amounted
14.3%35.
Another exercise training intervention, in which training consisted of
individually tailored strength-based exercises and aerobic activities
(modified every 3-4 weeks), showed no significant improvement in mental
health nor in objective neurocognitive functioning. By contrast,
self-reported measures of community use, home living, health and safety,
leisure, and self-direction did improve. Thirty-five percent of the
participants dropped out of the study and one fall without physical
injury was reported40.
A last exercise intervention implemented physical activity (strength,
endurance, and speed exercises) with simultaneous attentional challenges
(verbal stimuli). The exercise intervention was administered as a period
of physical training followed by a period of combined training or
reversed. Improvements were seen in all groups for verbal long-term
memory (baseline compared to post-intervention), as well as for
organization, and anxiety and emotional control (post-observation
compared to post-intervention). Additionally, they found no difference
between patients on or off cancer treatment They did not report on
adverse events and drop-out rate was 16.7%13.
Finally, eurythmy therapy is a form of mind-body therapy. One study
demonstrated that all patients (n=7) completing 25hours of eurythmy
therapy in a period of six-months, improved in full-scale IQ and
processing speed. Working memory (WM), perceptual reasoning, verbal
comprehension, and visual motor integration improved in six, five,
three, and five patients, respectively. This study did not report on
adverse events36.
Cognitive training
Regarding cognitive training, six articles (5 study populations)
employed the adaptive computerized working memory (WM) training,
Cogmed26–28,31,37,38. Participants receiving Cogmed
training showed improvement on attention, processing speed, WM, symbolic
WM and executive functions immediately
post-intervention27,28,31. WM scores and fluent
cognition were improved at 9.1 weeks post-intervention, and improvement
on fluent cognition remained stable at 14.5 weeks 38.
Improvement on processing speed, executive functions WM, visual-spatial
WM, academic achievement, emotional and behavioral problems, and social
skills and remained stable at six months
post-intervention27,28,38. In contrast, scores on two
attention tasks changed over time: spatial span forward (WISC-V)
deteriorated and omissions on the CPT improved27,28.
Finally, most stable improvement over time was observed for fluent
cognition and executive functioning at 13.5 months
post-intervention38.
No difference was observed between adaptive and non-adaptive Cogmed
training38. Compared to a non-adaptive WM training
(MegaMemo), adaptive Cogmed training did show greater improvement in
parent-reported learning difficulties26. Adaptive
Cogmed did not show a difference in WM improvement compared to JumpMath
(a workbook program directly targeting math skills), however the
improvement in mathematics (greater improvement for JumpMath group) and
symbolic WM (greater improvement for Cogmed group) was different among
these interventions 31. Higher pre-intervention IQ and
greater number of completed sessions predicted greater post-intervention
improvement26,28. Nevertheless, there was no
significant difference between 25 and 35 Cogmed
sessions37 .
Functional MRI (fMRI) found that Cogmed training reduced activation of
lateral prefrontal, left cingulate and bilateral medial frontal regions
during a WM task, however, this was not associated with WM
outcome27. Adverse events concerning Cogmed were
either not reported, or the study stated that no adverse events had
occurred26,28,37. Drop-out rates varied between 4.8%
to 25%.
Another computerized intervention, Fast ForWord, focuses on training
reading skills. This training effect was investigated in medulloblastoma
patients during radiotherapy. Compared to the standard of care group, no
significant differences were observed immediately post-intervention. At
subsequent follow-up timepoints (up to five years post-intervention),
specifically greater sound awareness was encountered at 2.9 years (range
1.6 – 4.5 years) post-intervention14,15. Only 16.3%
of participants completed the prescribed sessions and 7.0% dropped-out
of the study14. Patients were excluded from the study
if they experienced an adverse event, however, it was not specified
whether patients discontinued for this reason.
A last game-like cognitive training intervention that was investigated
in pediatric brain tumors, was the Captain’s Log (n=9), designed to
improve multiple neurocognitive domains including memory, attention,
concentration, listening skills, self-control, and processing speed.
After on average 28.4 sessions (range 9-53), improvement was seen for
digit-span forward (WISC-III) and parent-reported attentional problems.
Results of the digit-span forward (WISC-III) task were positively
correlated with pre-intervention IQ. No adverse events were
reported29.
In addition to interventions focusing on improving neurocognitive
functioning, other interventions were identified with the aim of
teaching compensatory strategies. Two studies applied a cognitive
remediation program (CRP)17,18. CRP is a
therapist-delivered framework designed to reinforce multidimensional
aspects of attention processes, encompassing hierarchically graded
massed practice, strategy acquisition, and cognitive-behavioral
interventions17,18. Immediately post-intervention,
improvement on academic achievement, parent- and teacher-reported
attention and hyperactivity symptoms and attention, WM, memory recall,
and vigilance was observed in the CRP group17,18. fMRI
showed increased regional activity in the CRP group both immediately and
six months after intervention, and these patterns were more closely
resembling those of typical developing children18.
There were no adverse events reported17.
The cognitive rehabilitation curriculum (CRC) is an online training
focusing on cognitive flexibility, attention and WM. Participants showed
increased processing speed, cognitive flexibility, and verbal- and
visual memory immediate post-intervention. Additionally, fMRI
demonstrated increased activation in the inferior, superior, and middle
frontal gyrus compared to pre-intervention activation patterns. They did
not report on possible adverse events30.
Two therapist-delivered training programs were studied as well. The
first one was cognitive and problems-solving training, which targeted
broader metacognitive functions through educational therapy, cognitive
behavioral and rehabilitation approaches. Post-treatment improvements
were specifically significant for reported social skills scores and
quality of written expression. Adverse effects were not reported, and
drop-out rate amounted 25%25. The second one was a
survivor’s Journey, targeting executive dysfunctions through behavioral
problem-solving therapy and metacognitive strategies. A survivor’s
Journey showed to improve self-reported emotional QoL, parent reported
total QoL and physical QoL immediately after the intervention.
Furthermore, their exploratory analysis showed that intervention effects
varied based on age at diagnosis and pre-intervention IQ. No information
was provided regarding adverse events. Only 10.5% dropped-out of the
study32.
Finally, the last cognitive training is neurofeedback training. This
training targets specific beta frequencies associated with arousal and
attention. Bot the intervention- and placebo- group showed
post-intervention improvement, without significant effect of the
neurofeedback training. No serious adverse events were reported and
drop-out rate amounted 11.3%16.
Pharmacological interventions
Two pharmacological compounds, methylphenidate (MPH) and donepezil, have
been studied in patients with a PBT. MPH was studied in six articles.
Immediate neurocognitive response of a single MPH administration showed
a significant effect on selective attention, impulsivity, and cognitive
flexibility21. Immediate improvement in sustained
attention was assessed in two studies, but only significant in one study19,21. A 3-week crossover trial (placebo, low dose
MPH, and high dose MPH), showed improvement of parent- and teacher
reported scores on attention and cognitive problems, improved attention
deficit/hyperactivity disorder index for low and high dose
MPH20,22. Additionally, teachers reported improved
social and academic competences, less hyperactivity symptoms, and less
problem behavior. Though, less problem behavior was only seen in the
high-dose MPH group20,22. Finally, a 12-month study
with individually titrated MPH dose showed improvement in reported
measures of attention, hyperactivity, and attention
deficit/hyperactivity disorder in both the MPH- and the control group.
However, improvement was significantly larger for measures of attention
and attention deficit/hyperactivity disorder in the MPH group compared
to control23,24. Sustained attention and processing
speed were also significantly improved, and improvement in attention was
already present after 1 month with a rebound after 3
months23,24 Modest agreement was observed between
parent- and teacher- ratings, and poor agreement was observed between
reported ratings and performance-based measures23,24.
Studies reported various adverse events in the MPH group as well as in
the control group. Reported adverse events included abdominal pain,
appetite loss, wheezing, dizziness, anxious, tearful, and many
more19–21. The range of reported drop-out rates was
between 10.5% and 33.8%19,20,23,24.
Donepezil, an acetylcholinesterase inhibitor, was described in one study
and showed significant improvement on executive functioning immediately
post-intervention, and these improvements persisted after a wash-out
period of 12-weeks. Additionally, moderate improvements in
parent-reported planning/organizing, WM, and memory were seen. The
drop-out rate was 27.3%. Several adverse events were reported, 30% of
the participants reported gastro-intestinal problems and 17% reported
non-specific mood changes and confusion. Nevertheless, 75.0% of
patients preferred re-administration after treatment completion because
of perceived benefit39.