Chapter

Cancer

9 Iris Paltin, Darcy E. Burgers, Marsha Gragert, and Chad Noggle

Introduction primary types of leukemia include acute lymphocytic

leukemia (ALL), chronic lymphocytic leukemia, acute
Cancer involves a number of diseases characterized by
myeloid leukemia, and chronic myeloid leukemia.
abnormal cell division and proliferation. Benign
The two most prevalent forms of lymphoma, which
tumors (neoplasms) are not cancerous; they are
is cancer of the lymphocytes of the immune system,
abnormal tissue growths that do not invade other
are Hodgkin lymphoma and non-Hodgkin
structures. The greatest risk associated with benign
lymphoma.
neoplasms is their location, because they may impact
Solid tumors within the adult population most
vital structures and vessels. Malignant neoplasms are
frequently include carcinomas (tumors of the skin,
cancerous and can spread to other parts of the body.
organs, and glands such as lung, breast, and prostate,
Malignant neoplasms are divided into low grade and
along with colorectal cancers) and sarcomas (tumors
high grade. The three broad groups of cancer include
of the bone, muscle, fat, and connective tissue). Solid
central nervous system (CNS) tumors, liquid tumors,
tumors within the pediatric population most fre-
and non-CNS solid tumors.
quently include neuroblastoma, Wilms tumor (kid-
CNS tumors involve the brain and spinal cord.
neys), rhabdomyosarcoma (soft tissues such as
Children generally develop primary CNS tumors,
muscle), osteosarcoma (bone), and retinoblastoma
which arise directly from the brain and spinal cord.
(eye). As is detailed in the Epidemiology and
Adults often develop CNS tumors via the metastatic
Pathophysiology section, the prevalence of cancer
process of cancerous cells being carried through the
types is dramatically different in pediatric versus
blood to the nervous system from another primary
adult populations.
site, such as the lungs. CNS tumors are further classi-
fied by location and type. CNS tumor locality can be
divided into (1) the skull, (2) the meninges, (3) the Epidemiology and Pathophysiology
cranial nerves, (4) the supporting tissue, (5) the pitui- In 2016, more than 1.6 million new cases of cancer
tary or pineal body, (6) congenital origin, and (7) were diagnosed in the United States, and more
supratentorial versus infratentorial. Brain tumor than 15,000 of these involved children and adoles-
types are gliomas, meningiomas, schwannomas, pitui- cents (US Cancer Statistics Working Group, 2016).
tary adenomas, primary CNS lymphoma, and meta- Currently, the most common adult cancers are
static tumors. Gliomas are further divided into breast cancer, lung and bronchus cancer, prostate
astrocytomas, ependymomas, glioblastomas, medul- cancer, colon and rectum cancer, bladder cancer,
loblastomas, and oligodendrogliomas. Although the melanoma of the skin, non-Hodgkin lymphoma,
histology of gliomas is the same between children and thyroid cancer, kidney and renal pelvis cancer,
adults, the incidence of tumor types and location is leukemia, endometrial cancer, and pancreatic can-
radically different. cer. With respect to pediatric cancers, ALL is the
Liquid tumors are cancers that involve the blood most common, accounting for approximately 20%
and lymphatic systems, and include leukemia and of all cancers, followed by CNS tumors (18%),
lymphoma. Leukemia is a cancer that causes abnor- Hodgkin disease (8%), non-Hodgkin lymphoma
mal blood cell production. Abnormal production of (7%), acute myeloid leukemia (5%), neuroblastoma
lymphoid white blood cells is called lymphocytic leu- (5%), bone tumors, and other cancers each
kemia, and abnormal myeloid white blood cell pro- accounting for 3% or less (American Cancer
duction is called myelogenous leukemia. The four Society, 2014).

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 Cancer

Sixty percent of children who survive cancers (of drowsiness, which progresses to coma; dilation of the
all diagnoses) experience late effects, such as inferti- pupils, which fail to react to light; and papilledema.
lity, heart failure, secondary cancers, and neuropsy- Convulsive seizures, focal or generalized, occur with
chological sequelae. Chemotherapy-related cognitive cerebral hemisphere tumors and may precede other
dysfunction is reported in 15–70% of adult patients symptoms by months or years. Treatment-related
(Bender et al., 2006), with approximately 30% of factors including surgical interventions, chemothera-
patients reporting long-term residual chemotherapy- pies, and cranial radiotherapy (CRT), contribute to
associated deficits (Ferguson & Ahles, 2003). neuropsychological sequelae.
Neurocognitive difficulties can be transient during Surgical interventions for CNS tumors include
treatment or can also be longer lasting, with late- biopsy, resection, and procedures to address asso-
emerging and long-term cognitive deficits (termed ciated neurologic complications (e.g., shunt place-
“late effects”) particularly prevalent in childhood can- ments and revisions, ventriculostomy). It is
cer survivors. Increased survival rates achieved important to note that the contribution of postsurgi-
through development of more effective cancer treat- cal cerebellar mutism to neuropsychological out-
ments have led to increased attention to such late comes has likely been underappreciated in the
effects. At the same time, disparities in pediatric can- existing literature, although increased emotional labi-
cer survival exist, with African American children and lity, ataxia, and hypotonia, as well as protracted cog-
those from the West and South of the United States nitive, academic, and psychosocial impacts, are
demonstrating higher mortality rates (Lindley & described.
Oyana, 2016). Higher mortality rates have also been Research evaluating cancer-related cognitive
reported in African American adults and those from impairment (CRCI) in the adult population has
lower socioeconomic strata (O’Keefe, Meltzer, & more traditionally focused on neurotoxicity asso-
Bethea, 2015). ciated with chemotherapy, a phenomenon often
referred to as ”chemobrain.” These CRCIs include
Disease and Treatment Factors Impacting problems in attention, concentration, memory, and
executive functioning and they have has also been
Functioning documented in the absence of chemotherapy, leading
The neuropsychological late effects of pediatric cancer to hypothesized associations with cancer itself
that extend into adolescence and adulthood, as well as (Debess, Riis, Pedersen, & Ewertz, 2009), surgery
the neurocognitive impact of cancer when diagnosed (Chen, Miaskowski, Liu, & Chen, 2012), and other
in adulthood, are associated with location, treatment- adjuvant therapies (Schilder et al., 2010).
and nontreatment-related factors. Brain tumors and Longitudinal studies evaluating neuropsychological
ALL are the most studied conditions with respect to outcomes in patients with cancer suggest that up to
neuropsychological late effects due to the direct 30% of patients experience CRCIs before any treat-
impact of disease and treatment on the CNS. ment (Janelsins et al., 2011). Up to 75% of patients
Location results in variability of neuropsychologi- experience CRCI during active treatment and up to
cal presentation and outcome. Brain tumors carry the 35% experience CRCI months or years after comple-
potential for virtually any neurological or neuropsy- tion of treatments for cancer (Janelsins et al., 2011).
chological sign. Prediagnosis symptoms result from As noted by Wefel, Kesler, Noll, and Schagen (2015),
regional infiltration of the tumor, mass effect, and the pattern of CRCI differs across patients and disease
increased intracranial pressure caused by tumor course, and severity typically qualifies as mild to mod-
growth and blockage of the flow of cerebrospinal erate (i.e., performances that are from −1.5 to −2
fluid through the ventricles. In some cases the tumor SDs below population normative means). CRCI also
presses upon or destroys parts of the brain, gradually varies in domains affected; may be subtle or dramatic,
increasing effects as the tumor grows. Consequently, temporary or permanent, stable or progressive; can
common symptoms of intracranial tumors include onset acutely or in a latent fashion; and can resolve
headaches, especially after lying flat, increased by quickly or persist for 20 years posttreatment (Ahles,
coughing or stooping; vomiting, which usually occurs Root, & Ryan, 2012; Koppelmans et al., 2012). These
at the peak of the headache; diplopia; blurred vision cognitive symptom are associated with fatigue,
when moving the head; slowing of the pulse; increased depression, and perceived health status (Li, Yu,

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

Long, Li, & Cao, 2015; Vardy et al., 2014) and are regions using diffusion tensor imaging (de Ruiter
negatively related to job performance, work ability, et al., 2012; Deprez et al., 2011).
productivity, and sustainable work (Munir, Burrows, Although chemotherapy is generally believed to be
Yarker, Kalawsky, & Bains, 2010; Von, Habermann, less toxic than CRT within pediatric cohorts, the addi-
Carpenter, & Schnieder, 2013). tion of chemotherapy with CRT may confer declines
Chemotherapy in adults has in one way or another in cognition (e.g., learning and memory) beyond
been associated with mild reductions in cognitive those associated with CRT alone (Di Pinto, Conklin,
functioning compared with controls across most cog- Li, & Merchant, 2012). With respect to non-CNS
nitive domains. However, the most common pattern cancers, the strongest evidence for adverse neuropsy-
of cognitive deficits associated with chemotherapy chological effects of chemotherapy alone has been
suggests preferential dysfunction of frontal subcorti- documented in survivors of ALL who receive intrathe-
cal networks, including changes in working memory, cal and high-dose intravenous methotrexate for stan-
executive functions, and processing speed (Janelsins, dard-risk disease (Hearps et al., 2016). However,
Kesler, Ahles, & Morrow, 2014). studies have also documented adverse neuropsycho-
Certain factors have been associated with logical effects of corticosteroids (Mrakotsky et al.,
increased risk of chemotherapy-induced neurotoxi- 2011), and the inclusion of vincristine and platinum-
city. These include but are not limited to (1) additive based agents is associated with peripheral neuropathy
or synergistic effects of multimodality therapy that and ototoxicity, respectively, which can increase risk
includes administration of chemotherapy either con- for cognitive and academic difficulties during
currently with or subsequent to CRT, (2) additive or survivorship.
synergistic effects of multiagent chemotherapy, (3) Hematopoietic stem cell transplant (HSCT) is
exposure to higher dosing due to either planned use another treatment-related risk factor that has received
of high-dose regimens or higher concentrations of the empirical attention in the pediatric cancer outcome
parent drug and/or its metabolite secondary to dis- literature. There is mixed evidence of its contribution
rupted systemic clearance and/or pharmacogenetic to cognitive outcomes above and beyond that con-
modulation of drug pharmacokinetics, (4) intraarter- ferred by other known risk factors (Willard, Leung,
ial administration with blood–brain barrier disrup- Huang, Zhang, & Phipps, 2014), but the evidence
tion, and (5) intrathecal administration (Noggle & generally suggests a relatively benign outcome.
Dean, 2013; Sul & DeAngelis, 2006; Taphoorn & There are physiological and psychological demands
Klein, 2004). In the case of chemotherapy, these def- of HSCT that have potential to affect health-related
icits arise through both direct and indirect neurotoxic quality of life. Evidence does support an early effect on
routes. The latter includes those cognitive issues that health-related quality of life after HSCT, but the
arise from physiological states such fatigue, anemia, longer term outcomes are not well studied and likely
and metabolic abnormalities. vary based upon a host of methodological (e.g., instru-
The literature to date has demonstrated both mentation) as well as child-related (e.g., age, gender)
structural and functional changes in the brain in rela- and family-based (parent emotional distress) risk
tion to chemotherapy. Cross-sectional studies indi- factors.
cate that adult patients treated with previous In cases of HCST within the adult population,
chemotherapy have more gray matter and white mat- Friedman and colleagues (2009) revealed that there
ter volume loss than controls, reduced white matter is a high rate of cognitive impairment (39%) before
integrity, and altered brain activation (Janelsins et al., HSCT. Approximately one-quarter of the sample par-
2014). Findings of reduced overall gray matter volume ticipated in serial evaluations, with a subset of patients
appear to be most pronounced in the prefrontal lobe; demonstrating worsening cognitive performance up
however, reduced temporal (e.g., thalamus, hippo- to 28 weeks after HSCT. Cognitive decline was not
campus, parahippocampal region), parietal and occi- accounted for by either baseline or concurrent mea-
pital (e.g., precuneus), and cerebellar cortical volume sures of quality of life, depression, or anxiety but
have also been found via magnetic resonance imaging lower education and older age were predictive of base-
(MRI) techniques (McDonald, Conroy, Ahles, West, line impairment (Friedman et al., 2009). In another
& Saykin, 2010). Decreased white matter integrity and study, Jones and colleagues (2013) found that 47% of
diffusivity have also been noted in widespread brain their sample exhibited cognitive impairment

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 Cancer

postinduction. Impairment continued to be high over Adults who receive radiation therapy also experi-
time: nearly 49% of patients at 1 month and 48% at 3 ence neurocognitive deficits and structural changes
months post-HSCT exhibited deficits on one or more on imaging. In the case of both neurocognitive func-
measures. Learning/memory showed the greatest vul- tioning and structural changes, a dose-dependent pat-
nerability to impairment at all three time points. tern is also observed in adults, with total dose and
Executive function showed greater vulnerability at dose per fraction influencing the severity of outcomes.
the pre-HSCT time point, motor function at 1 Adjuvant chemotherapy also increases the burden on
month post-HSCT, and psychomotor speed at 3 patients. Effects can be minimized, however, by keep-
months post-HSCT. ing the radiation dosing below 2 GY per fraction. Even
The evidence for neuropsychological impact of when taking these factors into consideration, acute
surgery, chemotherapy, and HSCT notwithstanding, and chronic impairments are commonly reported,
CRT has been associated with the greatest risks, with some deficits (e.g., attention, memory, informa-
although much variance in outcomes remains unac- tion processing, executive functioning, and motor
counted for in the existing literature. In pediatric coordination) developing in a latent fashion, over
cancer, long-term neuropsychological effects related the course of a few weeks, to months, to even years
to CRT appear to be mitigated by CRT dose, volume, after treatment (Habets et al., 2016). Functionally,
and type. Younger age at treatment and increased within the adult population, memory has demon-
time since treatment are risk factors for adverse neu- strated particular susceptibility to the effects of CRT.
ropsychological sequelae (de Ruiter, van Mourik, In addition to CRT and chemotherapy, endocrine/
Schouten-van Meeteren, Grootenhuis, & Oosterlaan, hormonal therapy has also been associated with neu-
2013; Palmer et al., 2013). See Tables 9.1 and 9.2 for rocognitive deficits. Such treatments include the use
additional information regarding radiation’s impact of estrogen deprivation treatment within the breast
on structural and functional aspects of cognitive func- cancer population and testosterone deprivation
tioning including attention, working memory, verbal within the prostate cancer population. In the case of
fluency, processing speed, memory, and vocational prostate cancer, testosterone has been linked with the
abilities. development and growth of the disease. As a result,
Other factors that may moderate neuropsycholo- androgen deprivation therapy (ADT) has proven
gical outcomes include CNS tumor histology and effective in treating prostate cancer, particularly in
location, neurologic/medical complications (e.g., cases postradiation. Although the antineoplastic ben-
hydrocephalus, seizures, endocrine dysfunction), efits of ADT are unquestionable, the treatment has
child-specific factors (e.g., higher baseline cognitive been associated with cognitive deficits and even psy-
functioning, female gender), and family factors (e.g., chiatric manifestation for which anxiety and depres-
lower socioeconomic status [SES], higher parent sion are the most commonly reported. Research
stress) (Kullgren, Morris, Morris, & Krawiecki, 2003; evaluating the cognitive effects of androgen depriva-
Palmer et al., 2013; Reddick et al., 2014). tion in patients with prostate cancer has produced
Effects on the microglial and microvasculature mixed results, with some studies showing no effect
environments, neurogenesis, neuroinflammatory (Joly et al., 2006), others demonstrating impaired
responses, and apoptosis constitute potential under- function (Jenkins, Bloomfield, Shilling, & Edginton,
lying mechanisms in the pathophysiology of CRT- 2005), and a mixed effect with patients showing an
induced neuropsychological sequelae. These effects improved performance on some tests and
can culminate in cortical and subcortical white matter a deterioration on others (Salminen et al., 2003).
changes, which have received the most attention in Functional MRI showed that compared with partici-
the literature (Mabbott, Noseworthy, Bouffet, Rockel, pants who did not receive ADT, patients with prostate
& Laughlin, 2006), with increased treatment intensity cancer undergoing ADT did not differ in cognitive
associated with reduced white matter volumes performance, but they showed altered prefrontal cor-
(Reddick et al., 2014). Direct correlations between tical activation during cognitive control (Chao et al.,
normal-appearing white matter and neurocognitive 2012). Chao and colleagues (2013) observed
outcomes, including IQ, math, and verbal working a decrease in gray matter volumes in frontal and
memory, have also been reported (Jacola et al., 2014; prefrontal cortical structures associated with the use
Mabbott et al., 2006). of ADT. The decrease in gray matter volume of the

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

Table 9.1 Clinical Manifestations of Cancer and Neuroanatomical Correlates

Neuropsychological Clinical Manifestation Neuroanatomical Correlates and Moderating

Domain Factors
Intellectual • Lower global, verbal, and visuospatial • Associated with
functioning intellectual abilities1,2,3,4,5,6,7 • reduced temporal-occipital connectivity6
• increased activation of the left inferior
frontal gyrus6
• NOS3 894 T homozygosity5
• Reduced white matter volume1,46
a

Attention and • Reduced attention and processing speed • Attention deficits associated with:
executive functions on performance-based and parent/ • Leukoencephalopathy and reduced
teacher report and slower reaction time1, caudate volume6
8,13,18,19
a
• White matter changes
• aReduced attention14
• aWorking memory deficits5,10,11,13,17 • Working memory deficits associated with
• aReduced attention, verbal fluency, and • leukoencephalopathy6,31
motor speed5 • increased activation in left superior/middle
frontal gyri and left parietal lobe6,12
• decreased BOLD signal in bilateral frontal
regions
• greater BOLD signal in left cingulate
regions15
• increased dorsolateral prefrontal cortex
and anterior cingulate cortex activation
during working memory tasks3,4,16,15
• COMT gene5
a
• increased RT dose more impactful than
brain metastases43
a
• dysfunction of frontal subcortical
networks47
• Disrupted folate pathways of MTHFR
1298AC/CC5
• Worse executive function associated with
microbleeds25
• aCOMT enzyme Val158 Met variant associated
with weaker performance5
• Genetic polymorphisms of inflammation,
a

DNA repair and metabolism pathways20

Processing speed and • Lower processing speed and motor • aGenetic polymorphisms of inflammation,
motor skills abilities compared to estimated IQ1,2,3,17, DNA repair, and metabolism pathways20
18,19,28,22,23,24
• Decrease in gray matter volume of primary
a

• Reduced motor and psychomotor

a
motor cortex51
speed44
Memory • Verbal and visual memory impairments4, • Weaker verbal memory associated with
14,21,26,28
• reduced amygdala and caudate
• aVerbal and visual memory impairments4, volume6
14,21,26,28,43,45,
• increased activation in left inferior frontal
gyrus6
• smaller right hippocampus27

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Table 9.1 (cont.)

Neuropsychological Clinical Manifestation Neuroanatomical Correlates and Moderating

Domain Factors
a
• cortical hypometabolism on PET and MRI,
when compared with scans in women not
taking tamoxifen52
• Weaker visual memory associated with
• abnormal and inefficient activation and
deactivation of the anterior rostral medial
prefrontal cortex and thalamus28
• aApo E genotype5
• aSignificant decline in neurogenesis in the
subgranular zone53
• Increased hippocampal dose associated with
a

reduced memory45
Academic and • Poorer performance on reading, spelling, • Reading deficits may be associated with
vocational and math tasks1,4 reduced white matter volume29,30,31
functioning • Reduced job performance, productivity,
and sustainable work48,49
Behavioral, adaptive, • Mixed findings; some support for higher • Lower SES associated with reduced adaptive
and psychosocial internalizing and externalizing functioning and increased behavioral
functioning, and symptoms31,32 symptoms41
fatigue • Increased risk for PTSD symptoms and • Homozygosity of the GSTM1 null genotype5
suicidal ideation33,34 • aAndrogen deprivation therapy associated
• Increased anxiety, depression, global with decreased gray matter volume in frontal
distress35,38 and prefrontal cortical structures54
• Reduced adaptive skills36
• Reduced educational/vocational
attainment37
• Increased social problems39,40
• aIncreased depression and anxiety50
• aFatigue is the most common reported
symptom among adults42
Note: BOLD = blood-oxygen-level dependent, PET = positron emission tomography, PTSD = posttraumatic stress disorder.
a
Denotes finding in adults.
1
Reddick et al., 2014; 2 de Ruiter et al., 2013; 3 Iyer et al., 2015; 4 Peterson et al., 2008; 5 Wefel et al., 2016; 6 Hearps et al., 2016;
7
Mabbott et al., 2006; 8 Moyer et al., 2012; 9 Gurney et al., 2009; 10 Palmer et al., 2013; 11 Knight et al., 2014; 12 King et al., 2015;
13
Kayl et al., 2006; 14 Pusztai et al., 2014; 15 Robinson et al., 2014; 16 Campbell et al., 2007; 17 Hiniker et al., 2014; 18 Kanellopoulous
et al., 2016; 19 Wolfe et al., 2012; 20 Liu et al., 2015; 21 Robinson et al., 2010; 22 Kahalley et al., 2013; 23 Palmer et al., 2013; 24 Annett et al.,
2015; 25 Roddy et al., 2016 26 Nagel et al., 2006; 27 Riggs et al., 2014; 28 Ozyurt et al., 2014; 29 Palmer et al., 2010; 30 Fouladi et al., 2004;
31
Jacola et al., 2014; 32 Buizer et al., 2006; 33 Brinkman et al., 2013; 34 Kazak et al., 2004; 35 Brackett et al., 2012; 36 Papazoglou et al., 2008;
37
Gurney et al., 2009; 38 Respini et al., 2003; 39 Willard et al., 2014; 40 Wolfe et al., 2013; 41 Robinson et al., 2015; 42 Hayes et al., 2013;
43
Chang et al., 2009; 44 Jones et al., 2002; 45 Gondi et al., 2012; 46 Mabbott et al., 2006; 47 Janelsins et al., 2014; 48 Munir et al., 2010;
49
Von et al., 2013; 50 Li et al., 2015; 51 Chao et al., 2013; 52 Eberling et al., 2004; 53 Monje et al., 2002); 54 Chao et al., 2013.

primary motor cortex correlated with increased population. Although tamoxifen can reduce recur-
response time on an N-back task, suggesting proces- rence and mortality, it has been linked with neuro-
sing insufficiency. cognitive deficits and complaints. In comparison
Tamoxifen is a selective estrogen receptor modu- studies between groups of patients treated with che-
lator that is commonly used in the breast cancer motherapy and those treated with hormonal

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

Table 9.2 Implications of Cancer-Related Neuropsychological Conditions for Clinical Practice

Developmental Assessment Intervention

Period
Childhood • Clinical surveillance and consultation with • Pharmacologic interventions (e.g.,
medical team regarding patient risk factors methylphenidate) may improve attention,
and potential evaluation behavior, and social skills
• Neuropsychological screening of at-risk • Neurocognitive intervention involving
patients (e.g., standardized self-/family acetylcholinesterase inhibitors may
report measures, computerized attenuate cognitive late effects
assessments) • Utilization of school liaison programming to
• Targeted or comprehensive increase knowledge about the survivor’s
neuropsychological assessment, including medical condition
performance-based assessment and self, • Cognitive remediation programming
family, and teacher reports on functioning • Social skills training
to identify late effects and provide specific • Encourage exercise
home, community and school • Implement family-based cognitive
recommendations interventions, including maternal problem-
• Psychosocial screening and support for at- solving intervention
risk patients and families • Link to social work and resource supports
Adolescence/ • Assessment and planning for transition • Provide education about importance of
Young readiness lifelong medical surveillance
Adulthood • Consideration of other risk factors that may • Individual therapy to address issues of
impact likelihood of assessing follow-up mood and identity
care • Link to social work and resource supports
• Assessment and monitoring of anxiety and • Telehealth opportunities
depression symptoms
Adulthood • Baseline and sequential assessment to • Individual and/or family therapy
monitor disease status • Utilization of support groups
• Comprehensive neuropsychological • Structured exercise programs and dietary
evaluations to identify late effects of plans
treatment • Complementary services (e.g., yoga,
• Distress thermometer screening tool to meditation)
assess psychosocial stressors • Pharmacological intervention to address
pain, sleep, fatigue, appetite, cognition, and
mood
• Telehealth opportunities

therapies, both groups show declines compared with (Schilder et al., 2010). This research also showed that
healthy controls suggesting that hormone therapies women with breast cancer taking tamoxifen demon-
can also lead to CRCI (Ahles et al., 2012). Research strated widespread cortical hypometabolism on posi-
has also demonstrated that combined treatment of tron emission tomographic and MRI scans, when
tamoxifen and chemotherapy leads to greater difficul- compared with scans of women not taking tamoxifen
ties than chemotherapy alone (Palmer, Trotter, Joy, & (Eberling, Wu, Tong-Turnbeaugh, & Jagust, 2004).
Carlson, 2008). One prospective study found dete- Beyond the neurotoxic effects of primary cancer
rioration in verbal memory and executive function therapy, the use of supportive medications (e.g., ster-
in postmenopausal patients taking tamoxifen for at oids, immunosuppressive agents, anticonvulsants)
least a year compared with healthy controls; those has also been tied to alterations in cognitive function.
taking the aromatase inhibitor, exemestane, did not Glucocorticoids, certain anticonvulsants (topiramate,
have significant deficits compared with controls phenobarbital), and analgesics used for pain control

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can all correspond with cognitive complaints and is thus considered to hold promise for reducing treat-
deficits. ment-related neurocognitive sequelae. Although over
Regarding nontreatment factors, there are broader the past decade PBRT availability for pediatric
social factors that impact outcomes. SES is an identi- patients has become much more widespread, the
fied moderator of neurocognitive outcome after number of patients who would be considered long-
pediatric ALL treatment, with SES associated with term survivors at risk for late effects remains small.
behavioral functioning 3–4 years after brain tumor Most available studies directly examining the cogni-
diagnosis (Kullgren et al., 2003). For pediatric brain tive risks associated with PBRT are hampered by
tumor survivors, among other variables, lower family methodological limitations, including small sample
income and lower parental education are associated sizes and/or lack of control group. These studies
with increased behavioral symptoms and reduced document outcomes ranging from no declines in
aspects of adaptive functioning (Robinson et al., Full Scale IQ to declines that are attenuated relative
2015). Similar findings have been noted in adults. to those documented after conventional RT, although
Minority ethnic groups and those of low SES are less with similar moderating factors (i.e., increased risk
likely to pursue recommended cancer screenings (e.g., for decline with young age and higher baseline per-
colorectal cancer screening, mammogram) and to formance) (Pulsifer et al., 2015; Yock et al., 2016).
receive cancer-reducing vaccinations (e.g., human The one available study to date to directly compare
papillomavirus vaccination), all factors that, in the the cognitive effects of conventional RT and PBRT
end, also contribute to higher cancer mortality rates also failed to provide clear evidence of cognitive spar-
(O’Keefe et al., 2015). ing after PBRT because significant IQ decline was
found in the conventional RT group but not the
Prevention PBRT group, yet the IQ slopes over time did not differ
Attempts to prevent or minimize neuropsychological between the two groups (Kahalley et al., 2016).
sequelae for pediatric patients with cancer have lar- Pharmacological prevention techniques, particu-
gely focused on reducing treatment-related neuro- larly those aimed at reversing treatment effects on the
toxicity. CRT has been eliminated from treatment microglial and microvasculature environments, neu-
protocols for patients with standard-risk ALL. With rogenesis, chronic inflammation, and apoptosis, may
respect to pediatric brain tumor (PBT) treatment, also hold promise based upon animal models. Lastly,
efforts have focused on limiting the dose and volume engagement in physical exercise has well-documented
of CRT, or on delaying CRT, to avoid the increased physical and emotional benefits that are important for
neurocognitive risk associated with younger age at pediatric cancer survivors, who as a group are at risk
treatment. Reduced craniospinal radiotherapy (RT) for cardiac and pulmonary late effects as well as socio-
doses have been shown to be associated with attenu- emotional difficulties. Given preliminary findings of
ated yet significant cognitive and academic decline a relationship between cardiorespiratory fitness and
(Ris et al., 2013). Other RT techniques (hyperfractio- executive functioning in survivors of PBT, exercise
nation) and chemoprotectants have been utilized to may prove promising in attenuating cognitive late
effectively increase the CRT dose delivered to the effects (Wolfe et al., 2013). Exercise could also coun-
tumor without increasing the associated toxicity. teract the pathophysiological effects of RT because of
Conformal CRT techniques reduce the volume of its ability to increase growth hormone and reduce
brain tissue exposed to radiotherapy. These techni- inflammation. Rodent studies have shown that exer-
ques do not entirely prevent healthy tissue surround- cise can ameliorate RT-induced deficits in both neu-
ing the target from being exposed to entrance and exit rogenesis and cognition. However, the evidence in the
radiation doses, and significant neuropsychological pediatric oncology literature is limited in that it pri-
sequelae continue to be documented, although marily relies on descriptive, pilot studies rather than
attenuation of impairment has been reported in randomized trials. Within that context, there is pre-
some PBT studies. liminary evidence that exercise-based interventions,
Recently, proton beam RT (PBRT) has replaced typically conducted during cancer treatment, are gen-
conventional photon radiation in PBT treatment pro- erally without adverse effects and positively affect
tocols at specialized treatment centers because it physical fitness and health-related quality of life out-
involves a lower entrance dose and no exit dose and comes in pediatric oncology (primarily ALL) sample

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

groups. Cognitive and motor skill outcomes have not irradiation plus cranial boost (average 25 Gy) before
received empirical attention. Adult oncology studies HSCT demonstrated average cognitive abilities
have also documented that exercise has a positive approximately 5 years after treatment completion,
impact on physical outcomes (i.e., fatigue, fitness, although processing speed and working memory
and strength) and quality of life (Mishra, Scherer, were relatively impaired (Hiniker et al., 2014).
Snyder, Geigle, & Gotay, 2016). Meta-analytic findings demonstrated that youth
Within the adult population, cancer prevention with ALL treated with chemotherapy only (including
includes limiting risk factors. This includes not intrathecal methotrexate) had significantly lower ver-
using tobacco products, eating a healthy diet, main- bal, performance, and Full Scale IQ scores relative to
taining a low body mass index, engaging in regular control groups (Iyer, Balsamo, Bracken, & Kadan-
exercise, limiting exposure to ultraviolet light, and Lottick, 2015; Peterson et al., 2008). A systematic
avoiding environmental carcinogens. At the same review of imaging studies revealed that ALL survivors
time, regular screenings for certain cancer types are treated with chemotherapy only demonstrated
important. Although such screenings do not pre- reduced attention, working memory, verbal memory,
vent cancer, they increase the likelihood of early visual memory and IQ, which was associated with
identification, which is often associated with treat- leukoencephalopathy; reduced amygdala, hippocam-
ment at a lower grade and stage, which, itself, has pal, and caudate volumes; and increased activation of
been associated with improved mortality and mor- the left inferior frontal gyrus and reduced connectiv-
bidity. Such screenings include mammograms for ity between the temporal and occipital lobes (Hearps
women, prostate exams for men, and colonoscopies et al., 2016).
for both men and women. These medical examina-
tions are in addition to self-exams that are encour- Attention, Working Memory, and Executive
aged: women checking regularly for lumps in their Functions. Survivors of PBT and ALL demon-
breast and men checking for lumps or nodules in strated worse attention on performance and parent
their testicles. and teacher report measures, including slower
reaction time (de Ruiter et al., 2013; Moyer et al.,
Clinical Manifestations 2012; Reddick et al., 2014). Among survivors of
The reader is directed to Table 9.1 for additional ALL and PBT, parent-reported attention problems
information and references describing structural and contributed to social functioning difficulties
functional associations of neuropsychological abilities (Moyer et al., 2012), suggesting that neuropsycho-
within the oncology population. This includes atten- logical deficits can also affect other realms of func-
tion and executive functions, processing speed, motor tioning and adjustment posttreatment. Despite
abilities, memory, social-emotional and adaptive preserved IQ, ALL survivors treated exclusively
functioning, and academic and vocational abilities. with chemotherapy and survivors of posterior
fossa tumors demonstrated deficits in processing
speed, executive functions, and working memory
Neuropsychological Functioning Among compared with peers (Kanellopoulous et al., 2016;
Pediatric Patients with Cancer Wolfe, Madan-Swain, & Kana, 2012). Less efficient
The late effects of pediatric cancer and treatment working memory is a consistent finding among
affect global intellect, executive functions, attention, survivors of PBT and ALL and is one of the
processing speed, memory, motor skills, academic more studied areas of neuroanatomical underpin-
achievement, and behavioral and psychosocial func- nings (Iyer et al., 2015; Palmer et al., 2013).
tioning (Palmer, 2008). Processing Speed and Motor Skills. Survivors of ALL
Intellectual Functioning. Compared with the norma- and PBT demonstrated significantly slower proces-
tive population, multiple meta-analyses highlight that sing speed and motor abilities compared with their
survivors of PBT (treated by a variety of modalities) estimated IQ, with contributing factors including
demonstrate lower global, verbal, and visuospatial high-risk disease, craniospinal irradiation, male gen-
intellectual abilities, especially if treated before the der, younger age at diagnosis, and increased time
age of 7 years (Reddick et al., 2014; de Ruiter et al., since diagnosis (Annett, Patel, & Phipps, 2015; Iyer
2013). Patients with ALL who received total body et al., 2015; Palmer et al., 2013).

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Memory. Children treated for medulloblastoma for ALL have higher parent-reported internalizing and
(necessitating CRT) and those treated for ALL treated externalizing symptoms and teacher-reported levels of
with chemotherapy only demonstrated verbal mem- externalizing symptoms (Buizer, de Sonneville, van
ory impairments (Peterson et al., 2008). Survivors of den Heuvel-Eibrink, & Veerman, 2006). Survivors of
craniopharyngioma revealed abnormal and inefficient PBT are at risk for increased posttraumatic stress
activation and deactivation of the anterior rostral symptoms (Kazak et al., 2004) and report higher levels
medial prefrontal cortex and thalamus when asked of suicidal thoughts compared with the general popu-
to recognize neutral and emotional faces (Ozyurt lation (Brinkman et al., 2013). PBT survivors also
et al., 2014). experience increased social difficulties, which may be
associated with cognitive difficulties, including execu-
Academic Functioning. Compared with controls, tive function weakness (Willard et al., 2014; Wolfe
survivors of PBT and ALL treated with chemotherapy et al., 2013). For survivors of cerebellar tumors, atten-
only performed significantly worse on reading, spel- tion span predicted communication skills, whereas
ling, and math tasks (Peterson et al., 2008; Reddick verbal memory predicted socialization skills among
et al., 2014), with visual-spatial and visual and verbal youth with third-ventricle tumors (Papazoglou, King,
short-term memory abilities predicting performance Morris, & Krawiecki, 2008). No indications of emo-
(Moore et al., 2016). Reading deficit in survivors of tional or behavioral difficulties were noted among chil-
PBT who received CRT has been associated with dren with a history of Wilms tumor (Buizer et al.,
reduced white matter volume, particularly in the 2006). Adolescent cancer survivors may be particularly
areas of the pons, internal capsule, and occipital and at risk for adjustment difficulties given the typical
temporal lobes (Palmer et al., 2010). In a cohort of stressors of this developmental period in addition to
children who received allogenic HSCT (diagnoses the late effects emerging at this time. Specifically, social
including ALL, acute myeloid leukemia, and nonma- and academic pressures may make coping with changes
lignant hematological disorders), weaknesses in pro- in physical appearance and academic abilities particu-
cessing speed and memory accounted for significant larly difficult.
variance in mathematics and reading abilities
(Lajiness-O’Neill et al., 2015). However, approxi- Longitudinal Outcomes. Longer term consequences
mately 12 years after a cohort of patients with ALL of pediatric cancer to consider include educational
who received total body irradiation before HSCT, achievement, employment, financial independence,
a majority had attended 2- or 4-year degree programs relationships, and independent living. Almost one-
(Hiniker et al., 2014). quarter of participants in the Childhood Cancer
Another likely underidentified risk group is chil- Survivor Study Cohort reported a history of receiving
dren with non-CNS solid tumors. Specifically, special education services, with survivors at greatest
approximately one-third of children with Wilms risk of using services if diagnosed at age 5 years or
tumor diagnosed before the age of 6 years reported younger; diagnosed with brain tumor, leukemia, or
academic difficulties, including failed grades, weak- Hodgkin disease; or if treated with intrathecal che-
ness on neuropsychological evaluation, and utiliza- motherapy and/or CRT (Gurney et al., 2009).
tion of formal individualized education plans Survivors of pediatric cancer are also at risk for not
(Mohrmann, Henry, Hauff, & Hayashi, 2015). completing secondary and postsecondary education
Inclusion of academic functioning measures or having full-time employment, with survivors of
should be considered not only for children and ado- brain tumors least likely to complete college (Gurney
lescents, but also young adults exploring postsecond- et al., 2009).
ary education (e.g., vocational, college, or graduate Relationships in adulthood are also affected by
education) who may require academic supports, pediatric cancer. Adult survivors of pediatric cancer
resources, and intervention. are less likely to be married, participate in social
activities, and live independently, particularly if they
Emotional, Behavioral, and Psychosocial experience physical limitations associated with diag-
nosis and treatment (Gurney et al., 2009), with an
Functioning increased risk of never having married among leuke-
There are mixed findings regarding emotional func- mia survivors and female patients treated with CRT
tioning of pediatric patients with cancer. Those treated (Gurney et al., 2009). Taken together, longer term
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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

educational, employment, and social outcomes of pretreatment, active treatment, and posttreatment
adult survivors of childhood cancer emphasize the phases with attention, processing speed, executive
effect of diagnosis and treatment across the transition functioning, and memory constituting the most com-
from childhood to adulthood. Such outcomes are mon difficulties at all time points. Yet such deficits are
important to consider among the adult survivor often not fully appreciated because commonly
population. employed screening measures such as the Mini-
Genetics. Emerging evidence suggests the importance Mental State Examination lack the sensitivity to detect
of genetic moderators of neuropsychological out- these residuals. As a result, a comprehensive, standar-
come. Genome wide association studies looking at dized neuropsychological approach, while being mind-
single nucleotide polymorphisms (SNPs) in pediatric ful of fatigue, is recommended. This approach also has
cancer survivors may help to identify patients at the benefit of addressing individual variability, parti-
increased risk for poor neurocognitive outcomes. cularly for those with direct CNS involvement,
This is of particular importance because children Inclusion of subjective report measures is also critical
have developing CNSs, and are especially vulnerable because patients may report greater impairments in
to treatment-associated effects on cognition. Primary everyday functioning than is revealed on objective
focus has been on evaluating SNPs of genes already assessment. Self-report measures pertaining to every-
believed to directly affect neural repair such as the day executive functioning, fatigue, and pain are highly
ApoE ε4 allele, which is associated with an increased recommended. Fatigue is particularly important to
risk of late-onset Alzheimer disease (Wefel, Noll, & assess via self-report given its direct influence on emo-
Scheurer, 2016). A study looking at 109 adult survi- tional, physical, and cognitive well-being. Such mea-
vors of childhood medulloblastoma using their sures may include the fatigue scales of the Patient-
healthy siblings as controls identified association of Reported Outcomes Measurement Information
homozygosity of the GSTM1 null genotype with System, the Fatigue Questionnaire, Fatigue Severity
increased anxiety, depression, and global distress Scale, or Multidimensional Assessment of Fatigue
(Brackett et al., 2012). The COMT gene involved in Scale.
the neurotransmitter pathway has also been asso- The neurological and neuropsychological
ciated with decreased verbal working memory in impairment resulting from metastatic lesions are
a cross-sectional analysis of survivors of childhood similar to those arising from primary brain tumors.
ependymoma and craniopharyngioma (Wefel et al., In many instances, cognitive features are seen later,
2016). Analysis of survivors of non-CNS cancers has as unrecognized tumors continue to grow.
also implicated genes associated with neurocognitive Interestingly, subtle changes in cognition can predict
function. Children with leukemia with nitric oxide recurrence and/or tumor growth before the tumor is
synthase 3 894 T homozygosity who are treated with recognized on imaging. Still, data suggests that non-
CRT may be more susceptible to intellectual function- specific neurocognitive deficits are present in
ing decline (Wefel et al., 2016). Survivors of upwards of 90% of patients (Tucha, Smely, Preier,
pediatric leukemia with disrupted folate pathways of & Lange, 2000). Approximately 91% of patients with
MTHFR 1298AC/CC genotypes may be at greater risk primary brain tumors will present with at least one
for executive dysfunction (Wefel et al., 2016). area of cognitive dysfunction at baseline and roughly
In summary, genome wide association-based 70% will present with at least three areas of dysfunc-
studies have identified specific genotypes of interest tion (Tucha et al., 2000). The frequency of cognitive
that might associate with decreased neuropsychologi- deficits emphasizes the role of neuropsychological
cal outcomes in pediatric cancer survivors. assessment in the care of patients. In fact, neuropsy-
chological assessment in some ways is more powerful
then neuroimaging. Meyers and Hess (2003) per-
Neuropsychological Functioning Among formed a baseline neuropsychological assessment
Adult Patients with Cancer on 80 patients with recurrent glioblastoma or ana-
In cases when cancer first develops in adulthood, cog- plastic astrocytoma before beginning a clinical trial
nitive deficits are common complaints of survivors. for recurrence. They found that 61% of patients
Interestingly, as suggested previously, cognitive deficits demonstrated measurable neurocognitive change
have been noted across all phases of care, including on assessment before imaging modalities,

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demonstrating significant change. This has been may even include assessments out to 1 year or more
noted in low-grade and high-grade gliomas as well after treatment, given that latency effects have been
as brain metastases (Meyers et al., 2004). reported. Again, given the potential impact of factors
such as fatigue and sleep disturbance, mood, medic-
Genetics. Investigation of the ApoE ε4 allele in inal changes and, anemia, these factors should be
a large cohort of adults with brain tumors revealed examined at the same time as the various assessments
an association of the Apo E genotype with neuro- to offer some control over their potential confounding
cognitive performance, specifically in learning, effects.
memory, and executive function (Wefel et al., When the purpose of the assessment is purely
2016). Other SNPs have been implicated in neuro- clinical, pretreatment assessment may still be strongly
cognitive outcomes. For example, the catechol- warranted, and it depends on the specifics of the case.
O-methyltransferase (COMT) enzyme Val158 Met Neuropsychological assessment has proven effective
variant has been associated with weaker in monitoring disease status. Consequently, this form
performance on measures of attention, verbal flu- of clinical tracking relies critically on baseline assess-
ency, and motor speed in chemotherapy-treated ment. When assessment is carried out during treat-
breast cancer survivors. Those adults with brain ment, just as in research, professionals should be
tumors with specific DNA repair pathway genes mindful of fatigue, mood, medicinal changes, anemia,
may have weaker processing speed and executive and other factors because they may have a direct
functions. In adults with high-grade glioma, influence on performance.
decreased neurocognitive function in the areas of
processing speed and executive functions has been Intervention in a Pediatric Population
associated with genetic polymorphisms of inflam-
Pharmacologic interventions are the most extensively
mation, DNA repair, and metabolism pathways (Liu
studied of the interventions available for survivors of
et al., 2015). The limitation of these studies to date
CNS-involved pediatric cancers, and methylpheni-
has been heterogeneity in tumor histopathology,
date has been the primary focus of this literature to
different treatment modalities, and lack of prospec-
date. The published studies have generated predomi-
tive longitudinal cohort study design.
nantly from two independent, randomized, double-
blind, placebo-controlled trials and document posi-
Role of Assessment tive, short-term outcomes on direct measures of
As described in earlier sections, pediatric assessment attention and parent/teacher ratings of behavior at
allows for monitoring of changing neurocognitive intervals up to 3 weeks after medication initiation
abilities over the course of development; allows plan- (Conklin, Helton, et al., 2010). Two nonrandomized
ning for home, school, and community supports; and studies have since collectively demonstrated that
informs the research literature about the extent of improvements are maintained at 12 months, with
neurotoxicity of different treatment modalities (e.g., specific evidence of improvement on direct measures
intrathecal chemotherapy, steroid use, photon vs. of attention, parent ratings of social skills and beha-
proton radiation). Assessment can include evaluation vioral problems, and parent, teacher, and self-report
near to diagnosis, and repeated evaluations during (adolescent subsample) ratings of attention (Conklin,
treatment and in the years after treatment comple- Reddick et al., 2010; Netson et al., 2011).
tion. Within adult settings, practitioners must be Neurocognitive intervention involving acetylcho-
mindful of the timing of assessment in conjunction linesterase inhibitors (Donepezil, Sunitinib) have
with the intended purpose. In the research setting, been the focus of various studies. Overall, these stu-
with most studies focusing on either the impact of dies have provided initial evidence that these agents
the disease itself or the treatment, pretreatment may improve cognition, health-related quality of life,
assessment is always critical. Depending on the addi- and mood in adults with cancer (Castellino et al.,
tional research interests, further assessments may be 2012; Shaw et al., 2006). In comparison, studies eval-
utilized. This could involve assessment during treat- uating the effectiveness of other psychoactive medica-
ment, immediately after the completion of active ther- tions (i.e., antidepressants, anticonvulsants, CNS
apy, and at key time points following treatment. This stimulants, and neuroleptic medications) are not

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

readily available in the literature even though their use pediatric cancer. Preliminary studies provided
in the cancer population does appear to be on the rise empirical support for a cognitive remediation pro-
(Brinkman et al., 2013). gram involving a tripartite model of rehabilitation
Beyond pharmacological interventions, various techniques, metacognitive strategies, and clinical psy-
cognitive and educational interventions have been chology techniques for survivors with CNS-involved
adopted in the clinical care of survivors of pediatric disease or treatments, but the results of a follow-up,
cancer. Two sets of published guidelines, including multicenter, randomized controlled trial were mixed
one by the Children’s Oncology Group, recommend (Butler, 1998; Butler et al., 2008), with small to med-
neuropsychological evaluation after completion of ium effect sizes on measures of academic achieve-
treatment or upon entry into long-term follow-up at ment, self-reported metacognitive strategy use, and
2 years posttreatment, and follow-up evaluations as parent (not teacher) ratings of attention. There was
clinically indicated thereafter (Annett et al., 2015; Noll no improvement on direct measures of neurocogni-
et al., 2013). However, empirical studies documenting tive functioning.
the efficacy of neuropsychological evaluation in In contrast to time- and resource-heavy clinic-
pediatric cancer are limited. Anderson, Godber, based interventions, online, computerized cognitive
Smibert, Weiskop, and Ekert (2000) reported training programs have been the focus of more recent
improved reading and spelling skills in survivors of investigations. Kesler, Lacayo, and Jo (2011) demon-
ALL between initial neuropsychological evaluation at strated significant improvements in processing speed,
2 years posttreatment and a follow-up evaluation 3 cognitive flexibility, and visual and verbal declarative
years later when the initial evaluation was accompa- memory as well as changes in functional MRI (fMRI)
nied by verbal feedback to parents and provision of activation patterns in the dorsolateral prefrontal
written information to both parents and school. Most cortex in a small sample of survivors of ALL and
recommendations in neuropsychological reports were PBT immediately after completing an online cogni-
not implemented. tive rehabilitation program developed by Lumos Labs
Children’s Oncology Group guidelines also (www.lumosity.com; San Francisco, CA). Another
recommend school liaison programming for survi- online program to remediate working memory,
vors of pediatric cancer with educational needs, and Cogmed (www.cogmed.com, Pearson Education,
many specialized pediatric cancer centers utilize such New York, NY), has been found to be feasible and
programs to facilitate school reentry, communication acceptable in samples of children ALL and PBT who
of information between the medical and educational have a history of CNS-directed therapies (Cox et al.,
teams, and implementation of educational recom- 2015; Hardy, Willard, Allen, & Bonner, 2013).
mendations. However, although various formal edu- In a randomized, single-blind, wait-list–controlled
cational interventions were the subject of several, trial of the 5- to 9-week Cogmed program in these
methodologically limited, empirical investigations samples (Conklin et al., 2015), the intervention was
more than a decade ago, no recent studies are avail- associated with benefit on direct measures of working
able. Within this context, the available studies docu- memory, attention, and processing speed as well as on
mented preliminary evidence of increased participant caregiver ratings of inattention and executive dys-
knowledge about the survivor’s medical condition, function. Training-related neuroplasticity was docu-
increased peer interest in interacting with mented in the left lateral prefrontal, left cingulate, and
a classmate who is a cancer survivor, and decreased bilateral medical frontal areas on fMRI. However,
personal worry about cancer. A more recent study of fMRI activation changes were not associated with
a direct math intervention in a sample of survivors of the cognitive changes, and improvements in proces-
ALL who received only chemotherapy documented sing speed did not generalize to measures of academic
specific improvements in calculation and applied fluency. Thus, although the research highlights the
math skills that were not evident in reading and spel- potential promise of cognitive remediation techni-
ling and were maintained 1 year after the intervention ques in children who have CNS disease or CNS treat-
(Moore, Hockenberry, Anhalt, McCarthy, & Krull, ment histories, studies investigating the maintenance
2012). and generalization of the associated benefits and their
Cognitive remediation programs have also been superiority to direct academic interventions are an
the focus of empirical research for survivors of essential next step before clinical adoption can be

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 Cancer

recommended. Similarly, neurofeedback was not sup- proceed through their treatment and even into survi-
ported as efficacious for survivors of PBT in a double- vorship. Depression and anxiety are by far the two
blind, randomized, placebo-controlled trial (de Ruiter most common psychiatric symptoms experienced
et al., 2016). within the cancer population. As with other medical
With respect to socioemotional interventions that ailments, the experience of prominent psychological
do not involve pharmacological agents, the pediatric distress in cancer has been linked with poorer out-
cancer literature focuses primarily in three areas: comes in terms of mortality and morbidity.
maternal problem-solving, posttraumatic stress, and Functionally, the negative impact of depression, anxi-
child social functioning. The efficacy of a maternal ety, as well as other such features has been extensively
problem-solving intervention for mothers of children described, including within the cancer population.
newly diagnosed with cancer has been established in The most effective way to address these issues is
multiple randomized controlled trials (most recently through psychosocial support in the form of indivi-
Sahler et al., 2013). A randomized wait-list control dual counseling for patients and loved ones, family
trial of a family intervention based in cognitive beha- counseling, and access to support groups. Cognitive
vioral and family systems theory targeting posttrau- behavioral therapy has been indicated in the treat-
matic stress symptoms among adolescent cancer ment of many of the physical and emotional sequelae
survivors, their parents, and their adolescent siblings of cancer and its treatment. Cognitive behavioral ther-
documented significant reduction of intrusive apy has demonstrated utility in treating depression,
thoughts among fathers and arousal among survivors anxiety, insomnia, quality of life, and even fatigue
(Kazak et al., 2004). Finally, investigations of survi- (Marcus, 2013). Structured exercise programs and
vor-directed social skills training in mixed cancer dietary plans have also demonstrated substantial uti-
groups have documented preliminary evidence of lity in improving depression, reducing anxiety and
their benefit on parent and child ratings of behavior stress, and improving fatigue (Vicari & Anton,
problems, parent ratings of school and social compe- 2013). Finally, complementary services such as yoga,
tence, patient ratings of social competence, and meditation, and massage therapy have all proven
patient perceptions of peer and teacher social support, effective in enhancing patient well-being.
and on direct social performance behaviors such as These intervention options are in addition to the
maintaining eye contact with peers, social conversa- symptom relief provided through more traditional
tions with peers, and cooperative play (Schulte, medicinal intervention. A detailed discussion of the
Vannatta, & Barrera, 2014). An emerging area of full spectrum of medications used within the cancer
investigation is social interventions that involve peer- population for symptom relief is well beyond the
mediated training in the classrooms of survivors, with scope of this chapter. Interested readers are encour-
available evidence demonstrating initial feasibility aged to see Sutton and Altomare (2013).
and acceptability of a classroom-based intervention Medicinal interventions may focus on reducing
that modeled appropriate ways to include, sustain pain and nausea or improving appetite, sleep, energy,
interactions with, and befriend isolated children. and cognition. Pharmacological interventions to
Preliminary evidence has documented a trend toward improve psychiatric status have also been discussed
increased peer-based friend nominations for PBT sur- extensively in the literature. Professionals working
vivors but not other (social acceptance, rejection, vic- with the population are encouraged to educate them-
timization) outcomes, and larger trials are warranted selves about not only these medicinal options, but also
to better elucidate the efficacy of such peer-mediated their contraindications within this population. Some
interventions (Devine et al., 2016). antidepressants, for example, interfere with the activ-
ity of chemotherapeutic agents, and vice versa.
Intervention in an Adult Population
Focused intervention within the adult oncology set- Implications for Clinical Practice
ting is multifaceted. Attention should be placed on
providing psychosocial support and symptom relief. Pediatrics
Within the clinical setting, once patients have As discussed, multiple factors contribute to risk for
a confirmed diagnosis, they may experience a wide neuropsychological impairment, including diagnosis
range of emotions that are constantly changing as they (brain tumor, leukemia), treatment and complications

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

(radiation, chemotherapy, shunts), individual factors generate tailored recommendations. The most in-
(age at diagnosis, time since treatment, gender), family depth and time-intensive option would be
factors (stress), and demographic characteristics (SES). a comprehensive neuropsychological evaluation that
There are key areas of vulnerability that require follow- would describe a patient’s broad profile of strengths
up and monitoring, including IQ, attention and execu- and weaknesses by including performance-based
tive functions (particularly working memory), proces- measures as well as self-, family, and possibly teacher
sing speed, memory, academic functions, and social- reports to implement broad recommendations at
emotional well-being. home, school, and in the community. Individuals
At the same time, as the number of survivors of who require targeted or comprehensive evaluations
childhood cancer grows there are limited resources will likely be monitored by a neuropsychologist every
(neuropsychologists) and practical pressures (insur- several years throughout childhood and into
ance preauthorization and cost) that influence the adulthood.
ability to provide the “right” type of service. As there are tiered levels of neuropsychological
Consequently, multiple groups have outlined stan- involvement, there are also tiered levels of psychoso-
dards and recommendations for monitoring survivors cial screening and support for patients and their
of childhood cancer, including the Children’s families. According to the Pediatric Psychosocial
Oncology Group, Psychosocial Standards of Care Preventative Health Model psychologists should pro-
Project for Childhood Cancer, and National vide consultation and intervention for those patients
Comprehensive Cancer Network. A clinical colla- and families with the highest risk factors and vulner-
borative of pediatric neuropsychologists recently pub- abilities, least resources, and greatest distress.
lished guidelines regarding different options for levels An example of an at-risk subset would include those
of care that would provide appropriate access for survivors with reduced cognitive abilities, specifically
patients (Baum et al., 2017). Neuropsychologists executive functions, because poor behavioral control
should consider their role within multidisciplinary is associated with increased parental stress (Patel,
teams, and how to maximize access and meet patient Wong, Cuevas, & Van Horn, 2013). At the same
needs appropriately. The following is a summary of time, because parental distress is a predictor of overall
the collaborative’s suggestions. survivor functional status, psychologists and neurop-
First, all patients can benefit from clinical surveil- sychologists could include discussion and screening
lance, which can be accomplished by multiple mem- of parental distress and family functioning during
bers of a medical team throughout treatment and clinical interviews in addition to questions targeting
survivorship to explore perceived cognitive or aca- cognitive and academic performance.
demic problems and investigate the need for neurop- More than 60,000 adolescents and young adults
sychologist involvement. Next, consultation can occur age 15 to 39 years are diagnosed with cancer in the
between a neuropsychologist and the medical team United States each year (American Cancer Society,
members and/or family members regarding potential 2014). Psychologists and neuropsychologists must
risks, evaluations, and interventions that could benefit pay particular attention to this population because
a patient. Third, neuropsychological screening can they are at specific risk for difficulties with adjustment
occur with identified at-risk patients (due to medical (if diagnosed in adolescents or young adulthood), as
team member observations, parent or self-report, well as demonstrating increased neurocognitive,
known risk factors) and includes standardized self- behavioral, and psychosocial sequelae due to treat-
or family report measures or computerized assess- ment (if treated in earlier childhood). Consequently,
ments administered by a range of medical team mem- the transition to independence in adolescence and
bers that would indicate the need for additional adulthood, including the transition to adult care,
assessment or intervention (e.g., neuropsychological requires understanding of a person’s cognitive abil-
evaluation, psychosocial involvement, alteration to ities, monitoring of anxiety and depression symp-
school supports). Fourth, targeted evaluation can toms, assessment and planning for transition
occur based on screening results and includes admin- readiness, and education about the importance of life-
istration and interpretation of performance-based long medical surveillance (Nathan, Hayes-Lattin,
measures by a neuropsychologist to answer specific Sisler, & Hudson, 2011). This also includes awareness
questions about cognitive functioning, and then of risk factors such as reduced educational and

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employment attainment, lower SES, lack of private to switch providers or as they transition in their care
insurance, difficulty with travel, and being to less regular checkups, it is not uncommon to
non–White are associated with reduced likelihood of observe fluctuations in their emotional status.
accessing follow-up care. Although within the clinical setting comprehen-
sive assessment is more essential, within the para-
Adults meters of a clinical study the desired end points may
Within the adult population, attention is placed on direct assessment in a more focused direction. In both
the methods used in the assessment of cognitive func- instances, the practicing clinician is encouraged to
tioning and ongoing assessment of psychosocial avoid lengthy assessment that extends beyond 2
needs. Practitioners are encouraged to remain mind- hours, given that this population is already susceptible
ful of the fact that patient functioning is constantly to fatigue, which will inevitably skew results.
changing. Within the realm of cognitive functioning, For a summary of assessment and intervention
as previously noted, screening tools such as the Mini- recommendations presented according to develop-
Mental State Examination are not adequately sensitive mental stage (childhood, adolescence/young adult,
to detect many of the cognitive sequelae that develop adult) the reader is referred to Table 9.2. Key areas
secondary to various forms of cancer and its treat- to assess or follow up with are IQ, attention and
ment. Self-report measures that assess subjective cog- executive functions, processing speed, motor skills,
nitive complaints can be useful from an identification memory, academic functions, adaptive functioning,
standpoint, although such measures often overesti- social-emotional well-being, and fatigue.
mate the extent of cognitive impairment. Sequential
assessment can prove useful not only in tracking cog- Future Directions
nitive status over time, but also in some cases noticing Future directions should focus on who should receive
significant changes that indicate disease progression increased attention, how neuropsychological
before it is fully appreciated on imaging (Janelsins functioning should be assessed, what to include in
et al., 2014). Research protocols are still needed to assessments, when to conduct assessments, and iden-
expand our understanding of the full utility of assess- tifying possible interventions with survivors and
ment in the ongoing care and assessment of patients families. An empirically validated model would
with cancer. allow for “rightsizing” neuropsychology services and
As to ongoing assessment of psychosocial needs, provide appropriate access to a larger number of
the National Comprehensive Cancer Network has patients and survivors (Baum et al., 2017).
spoken on the importance of regular, ongoing assess- To facilitate this clinical care, and to streamline
ment of psychosocial needs. The National research, it will be important to develop and imple-
Comprehensive Cancer Network Distress ment validated screening tools that can identify at risk
Thermometer is a screening tool that assesses psycho- patients based on treatment risk factors, personal and
social stressors ranging from physical complaints family characteristics, emotional well-being, SES,
(pain, fatigue, insomnia), to emotional complaints vocational/educational attainment, fatigue, physical
(depression, anxiety), to issues pertaining to social activity, sleep, and other factors so that both assess-
stressors such as financial burden or childcare con- ment and intervention resources are most effectively
cerns. The measure directs patients to rate their level deployed.
of acute distress and identify areas of concern. In our diverse society it is essential that care be
Because these issues can change over time, repeated culturally competent and language appropriate so that
assessment is recommended over the course of care, information is accurately communicated, and support
which emphasizes to patients that the focus of care and interventions engage wide support networks (e.g.,
extends beyond antineoplastic care, thus they are parents and extended family/community) to attain
more willing to discuss such issues with their oncol- functional survivor improvements (Bava, Johns,
ogy health-care providers. Establishing such an alli- Freyer, & Ruccione, 2016). Additional research is
ance is critical within the oncology setting. needed across all points of care, including prevention,
Establishing such close and trusting relationships as it pertains to health disparities across different
with their providers, in and of itself, is therapeutic groups. Similarly, clinical and research questions
for patients. Consequently, when patients are forced need to more rigorously incorporate family factors,

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 Iris Paltin, Darcy E. Burgers, Marsha Gragert, & Chad Noggle

such as family functioning and SES, to better under- samples from the domains of highest risk, while
stand how these variables impact survivor outcomes, mindful of the impact of fatigue on functioning,
and how these factors can be incorporated in inter- would accrue important data. It is imperative that
ventions. This is needed within both the pediatric and standardized research batteries include measures
adult populations. beyond IQ (e.g., attention, executive functions, pro-
Increasing emotional functioning screening, to be cessing speed, memory, mood), particularly because
employed by a wide range of medical team members, imaging and genetic studies have found correlations
could also provide important information about with attention, executive function, and memory, to
patient functional status. Emotional adjustment is better understand survivor needs and possible meth-
known to influence morbidity and mortality, and ods and times to intervene.
should be evaluated within both pediatric and adult Another option for standardized and widely avail-
populations. Over the course of treatment, the emo- able assessment is employment of computerized
tional well-being of patient, caregivers, and family assessments. These techniques must be comprehen-
may all go through significant shifts. Continued sive, abbreviated, and administered in a sequential
refinement is needed of the process by which these fashion without prominent practice effects. Several
outcomes are monitored, and how that information is computerized neuropsychological batteries have
used by the broader medical team. At the same time, been employed in the assessment of individuals with
the benefits of specialized care are well known but not cancer, including Cambridge Neuropsychological
always readily available. Consequently, research Test Automated Battery (CANTAB; Cambridge
should look into the feasibility, utility, and efficacy Cognition, Cambridge, UK, www.cantab.com),
of telehealth services to address the emotional needs Immediate Post-Concussion Assessment and
of patients with cancer. Cognitive Test (ImPACT; Lovell, 2016), and, more
Professionals trained in fields such as health psy- prolifically, Cogstate (Cogstate Ltd., Melbourne,
chology may not be readily available to patients in Australia, www.cogstate.com). Cogstate is increasing
rural settings. Teletherapeutic services could create an in popularity and accessibility across multiple disease
avenue by which these patients and their families can groups and age ranges (particularly in elderly popula-
be reached. Within the psychosocial realm this has tions). It has demonstrated acceptable sensitivity and
been seen in the development of the Patient-Reported neuroimaging correlations compared to traditional
Outcomes Measurement Information System, which neuropsychological batteries (Maruff et al., 2009).
permits practitioners to collect a wide array of clinical It is currently used in treatment (high-risk ALL) and
data pertaining to a patient’s physical, social, and neurocognitive intervention trials within the
emotional well-being, is feasible for adults and Children’s Oncology Group due to its demonstrated
young children with cancer to complete, and has validity, reliability, time limits, portability (laptop),
been translated into many languages to increase limited training required to administer, and ease of
patient access. As a result of the program employing multisite administration. Cogstate is also incorpo-
item-response theory as an underlying statistical rated into an on-study ALL trial at the Dana-Farber
tenant, the task is not time-consuming for the patient. Cancer Institute (Boston) and has shown correlations
Currently neurocognitive cancer research is ham- with biomarkers in hopes of identifying those at risk
pered by the wide range of measures employed, parti- for cognitive impairment and informing when to
cularly in pediatric cancer research. Uniform initiate intervention (Sands et al., 2016). For both
administration of a consistent battery (e.g., National pediatric and adult populations, it is imperative that
Institutes of Health NIH Toolbox for the Assessment within the research setting, initial assessments are
of Neurological and Behavioral Function [Gershon undertaken at the earliest possible point, before any
et al., 2013]; Children’s Oncology Group Protocol treatment intervention and tracked over time, permit-
ALTE 07C1: Neuropsychological, Social, Emotional, ting between-group and within-group comparisons.
and Behavioral Outcomes in Children with Cancer) At the same time, in nononcology settings there
enables comparisons of findings that can describe have been concerns about Cogstate’s unsatisfactory
impact of treatment and changes over time across reliability and validity estimates compared with con-
the developmental trajectory. A broadly accepted ventional neuropsychological assessments (Fratti,
abbreviated battery that is feasible to administer and Bowden, & Cook, 2016). There are also concerns

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related to the strong emphasis of reaction time and relationships) in conjunction with traditional assess-
speed and the reliance on a purely visual assessment. ment to better understand functional outcomes.
Assertions that visual reasoning, response rate, and Several areas of emerging intervention research in
executive functions are predictive of risk and/or long- pediatric care are promising. They include timing
term cognitive functioning ignores the potentially and extent of cognitive interventions, including cog-
separate and unique relationship of verbal function- nitive remediation, to both prevent possible late effects
ing during and after cancer treatment. and to ameliorate deficits that have emerged.
There are two patient groups that could specifi- In addition, a better understanding of how the family
cally benefit from increased access to neuropsycholo- understands neuropsychological reports is essential so
gical services. First, young children treated for solid a family can translate findings into effective support
non-CNS tumors (Sleurs, Deprez, Emsell, Lemiere, & and intervention strategies in the home, school, and
Uyttebroeck, 2016) may demonstrate greater func- community. Ongoing research into the role of family
tional impairment (e.g., failed grades) than has pre- management and functioning in supporting survivor
viously been appreciated. Second, survivors of growth (as is explored in the medical/traumatic brain
treatment including HSCT may face unique impacts injury and behavioral health/schizophrenia literature)
of treatment such as prolonged school or vocational is also warranted. When attempting to maximize pro-
absences. fessional resources and survivor outcomes, it is impor-
Practitioners can also adapt and increase the fre- tant to discover whether a school liaison increases
quency of conversations they have with adolescents survivor academic success. Early literature also sug-
and young adults regarding transition from pediatric gests that targeting social skills and social cognition
to adult care in survivorship. Awareness of unique may improve quality of life.
stressors and concerns of adolescents and young Both children and adults will benefit from finding
adults (including appearance, fertility, cognitive ways to improve sleep hygiene and sleep quality
impact, social isolation) is essential and will allow during and after treatment completion. This would
for the bridging of care between child and adult treat- be one important component of increasing quality of
ment teams. life by reducing fatigue. Improving ways in which
An additional path that must be taken moving treatment-induced fatigue is addressed is critical
forward is understanding the variability of response given its ramifications for overall well-being and
across patients to disease processes and interventions, quality of life for those with cancer. Other avenues
including the development of cognitive deficits. This where new interventions could mitigate the effects of
should include research on genetic and other biologi- fatigue may include increased physical activity and/
cal markers that correspond with patient response or the use of medication. In particular, more focus
and susceptibility. Preliminary research has been should be placed on nonpharmacological interven-
undertaken such as determining subsets of patients tions such as yoga and resistance training. Such
who are more sensitive to CRT. Such information can interventions affect other aspects of physical well-
be critical to treatment decision-making in the future. being and functioning, ranging from immune
For example, in cases where adult patients are identi- response to return-to-school and/or work issues.
fied as being radiation sensitive, a hippocampal- Overall, ongoing research that identifies specific at-
sparing approach may be taken that could reduce risk populations and maximizes the timing of inter-
residual cognitive burden (although, admittedly, ventions is an important next step.
treatment effectiveness could also be diminished in
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