Ebook Textbook of clinical neuropsychology (2/E): Part 2

23 Cognitive Functions in Adults With Central Nervous System
and Non-Central Nervous System Cancers
Denise D. Correa and James C. Root

Introduction

Brain Tumors

Cognitive dysfunction is common in many cancer patients
and can be related to the disease and to treatment with chemotherapy and/or radiotherapy (RT). The neuropsychological domains affected and the severity of the deficits may vary
as a result of disease and treatment type, but difficulties in
executive functions, motor speed, and learning, and retrieval
of information are the most prevalent. In a significant number of cancer patients, changes in cognitive functions interfere with their ability to resume work and social activities at
prediagnosis levels.
There has been an increase in the number of studies and
clinical trials that incorporate standardized cognitive outcome measures for the assessment of patients with cancer
of the central nervous system (CNS; see Correa, 2006;
Taphoorn & Klein, 2004). New developments have been
described in the study of the cognitive side effects of chemotherapy for non-CNS cancers (Correa & Ahles, 2008).
These lines of research have provided valuable information
about the incidence of cognitive dysfunction in patients with
various cancers, and the contribution of treatments involving
different regimens and modalities. Studies have also begun
to investigate the underlying mechanisms that may contribute to the neurotoxicity of RT and chemotherapy (Dietrich,
Han, Yang, Mayer-Proschel, & Noble, 2006; Nordal &
Wong, 2005) and interventions to minimize or prevent both
structural and functional damage associated with these regimens have been proposed (Gehring, Sitskoorn, Aaronson, &
Taphoorn, 2008).
The current chapter reviews studies involving patients
with brain tumors and breast cancer, considering that
most of the research has been conducted in these patient

groups. Of note, other emerging areas of study include
cognitive dysfunction associated with androgen ablation
for prostate cancer (Jamadar, Winters, & Maki, 2012;
Nelson, Lee, Gamboa, & Roth, 2008), chemotherapy for
ovarian cancer (Correa & Hess, 2012; Correa et al., 2012;
Correa, Zhou, Thaler, Maziarz, Hurley, & Hensley, 2010),
and high-dose chemotherapy and stem cell transplantation for hematological cancers (Correa et al., 2013; Syrjala
et al., 2011; Syrjala, Dikmen, Langer, Roth-Roemer, &
Abrams, 2004).

Primary brain tumors are classified by their predominant
histologic appearance and location; they account for less
than 2% of all cancers. Gliomas are the most common
primary tumors accounting for approximately 40% of all
CNS neoplasms (Greenberg, Chandler, & Sandler, 1999).
High-grade gliomas (WHO Grade III-IV) include glioblastoma multiforme, anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic mixed gliomas. Low-grade
gliomas (WHO Grade I-II) include astrocytomas, oligodendrogliomas, and mixed gliomas. Other less frequent brain
tumors are primary CNS lymphoma (PCNSL), ependymomas, meningiomas, and medulloblastomas (Bondy, El-Zein,
Wrench, 2005). Brain metastases are also common intracranial tumors in adults (Mehta & Tremont-Lukas, 2004)

Figure 23.1

Coronal and axial MRIs showing a brain tumor
involving cortical and subcortical regions


Cognitive Functions in Adults With Cancers
As effective treatment interventions have increased survival, there has been greater awareness that many brain tumor
patients experience cognitive dysfunction, despite adequate
disease control (Poortmans et al., 2003). This dysfunction

can be related to both the disease and its treatment including
surgery, RT, and chemotherapy. The side effects of medications such as corticosteroids and antiepileptics often contribute to or exacerbate these cognitive difficulties. The relevance
of including cognitive and quality of life (QoL) evaluations
as outcome variables in neuro-oncology research has been
increasingly recognized (Johnson & Wefel, 2013; Meyers &
Brown, 2006) and the National Cancer Institute (NCI) Brain
Tumor Progress Review Group report has recommended that
routine cognitive and QoL assessment become the standard
care for patients with brain tumors (BTPRG, 2000). Meyers
and Brown (2006) published guidelines for the neuropsychological assessment of patients with brain tumors within the
context of clinical trials. The suggested core neuropsychological test batteries include standardized instruments with
demonstrated sensitivity to the neurotoxic effects of cancer
treatment and include tests of attention, executive functions,
learning, and retrieval of new information, and graphomotor
speed (Correa et al., 2004; Wefel, Kayl, & Meyers, 2004). The
feasibility of incorporating a relatively brief cognitive test
battery in multi-institutional clinical trials within the context
of the Radiation Therapy Oncology Group (RTOG) has also
been demonstrated (Meyers et al., 2004; Regine et al., 2004).
Recent longitudinal studies documented that along with
age, histology, and performance status, cognitive functioning
is a sensitive and important factor in clinical trials involving
patients with high-grade tumors (Reardon et al., 2011; Wefel
et al., 2011). Performance on a test of verbal memory was
independently and strongly related to survival after accounting for age, performance status, histology, extent of resection,
number of recurrences, and time since diagnosis in patients
with glioblastoma or anaplastic astrocytoma (Meyers, Hess,
Yung, & Levin, 2000). Neuropsychological test performance
predicted survival in patients with metastases and leptomeningeal disease (Meyers et al., 2004), and glioblastomas (Johnson, Sawyer, Meyers, O’Neill, & Wefel, 2012; Klein et al.,
2003). Cognitive decline preceded radiographic evidence of

tumor progression by several weeks in glioma patients (Armstrong, Goldstein, Shera, Ledakis, & Tallent, 2003; Brown
et al., 2006; Meyers & Hess, 2003). However, these results are
interpreted with caution considering that some studies had
missing data, lacked a control group, and did not account
for the possible effects of medications (Mauer et al., 2007).
Disease and Treatment Effects
Seizures, headaches, increased intracranial pressure, focal
neurological signs, and cognitive impairment are common
presenting symptoms in patients with brain tumors. Several
studies documented cognitive impairment at diagnosis and
prior to RT or chemotherapy in patients with high-grade

561

gliomas (Klein et al., 2001), low-grade gliomas (Klein et al.,
2002), and PCNSLs (Correa, DeAngelis, & Shi, 2007). Cognitive difficulties present at the time of diagnosis are often
related to the location of the tumor (Klein et al., 2001), but
a diffuse pattern of deficits has also been reported (Crossen, Goldman, Dahlborg, & Neuwelt, 1992). Rate of tumor
growth is a predictor of cognitive impairment, as slow-growing tumors (e.g., low-grade gliomas) are often associated
with less severe cognitive dysfunction than rapidly growing
tumors (e.g., high-grade gliomas) (Anderson, Damasio, &
Tranel, 1990; Hom & Reitan, 1984). Tumor type or volume
has not been found to predict cognitive performance (Kayl &
Meyers, 2003).
Surgical resection can be associated with transient neurological and cognitive deficits due to damage to tumorsurrounding tissue and edema (Bosma et al., 2007; Duffau,
2005), with impairments often consistent with tumor location (Klein, 2012). Intraoperative stimulation mapping has
been used in patients undergoing surgical resection for gliomas, and a recent meta-analysis (De Witt Hamer, Robles,
Zwinderman, Duffau, & Berger, 2012) showed that the procedure was associated with fewer neurological deficits and
allowed for more extensive resections. However, the incidence
and extent of cognitive dysfunction related to tumor surgical resection is unknown, given the relatively limited number

of studies including pre- and postsurgical neuropsychological evaluations. In addition, the specific contribution of the
tumor to cognitive performance is difficult to ascertain
considering that the majority of patients receive corticosteroids and antiepileptic medications following diagnosis and
perioperatively. Steroids may improve cognitive deficits due
to resolution of edema (Klein et al., 2001), but can also be
associated with transient mood disturbance and working
memory difficulties (Bosma et al., 2007; Lupien, Gillin, &
Hauger, 1999). Antiepileptics can disrupt some aspects of
cognitive functions in brain tumor patients, particularly
graphomotor speed and executive abilities (van Breemen,
Wilms, & Vecht, 2007).

Whole-Brain and Conformal Radiotherapy
MECHANISMS OF CNS INJURY

The pathophysiological mechanisms of radiation injury
involve interactions between multiple cell types within the
brain including astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes (Greene-Schloesser, Moore, &
Robbins, 2013; Greene-Schloesser et al., 2012). Suggested
mechanisms include depletion of glial progenitor cells and
perpetuation of oxidative stress (Tofilon & Fike, 2000).
Radiation may diminish the reproductive capacity of the
O-2A progenitors of oligodendrocytes, disrupting the normal turnover of myelin. Blood-vessel dilatation and wall
thickening with hyalinization, increased blood-brain barrier


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Denise D. Correa and James C. Root

(BBB) permeability due to endothelial cell loss and apoptosis, and a decrease in vessel density have also been hypothesized to lead to white matter necrosis (Nordal & Wong,
2005; Warrington et al., 2013). The extent to which radiation
damage is due to direct toxicity on cells or secondary to
deleterious effects on the vasculature remains to be elucidated (Noble & Dietrich, 2002). Progressive demyelination
may take months to cause symptoms because of the slow
turnover of oligodendrocytes, contributing to the latency in
onset of neurotoxicity and its progressive nature. In addition, RT achieves therapeutic effects in part through DNA
damage by introducing interstrand DNA and DNA-protein
crosslinks, single- and double-stranded DNA breaks, methylation, oxidation, and by increasing formation of reactive oxygen species (ROS). Increased numbers of reactive
astrocytes and microglia have been shown to produce ROS,
proinflammatory cytokines, and growth factors that may
cause progressive inflammatory injury (Kim, Brown, Jenrow, & Ryu, 2008). The accumulation of DNA damage in
neuronal cells, when unrepaired, can lead to the transcription of defective proteins, apoptosis, and neurodegeneration
(Fishel, Vasko, & Kelley, 2007). Recent animal and human
studies have documented that RT, chemotherapy, and corticosteroids can disrupt hippocampal neurogenesis (Dietrich
et al., 2006; Fike, Rosi, & Limoli, 2009; Monje & Dietrich,
2012; Monje et al., 2007). RT produces elevation of inflammatory cytokines in the brain (Lee, Sonntag, Mitschelen,
Yan, & Lee, 2010), and inflammation surrounding neural
stem cells may contribute to neurogenesis inhibition (Monje,
Toda, & Palmer, 2003). RT-induced apoptosis and a decline
in neurogenesis in the subgranular zone of the dentate gyrus
were associated with deficits in hippocampal-dependent
tasks in some studies (Madsen, Kristjansen, Bolwig, &
Wortwein, 2003; Raber et al., 2004).
CLINICAL FINDINGS

Radiation encephalopathy has been classified into three
phases according to the time between the administration of
RT and the development of symptoms (DeAngelis & Posner,
2009). These are described as acute, early delayed, and late

delayed. Acute encephalopathy develops within days of RT
and the most common symptoms are nausea, headache, and
worsening of neurological signs. Disruption of the BBB by
endothelial apoptosis, increased cerebral edema, and intracranial pressure have been suggested as underlying mechanisms. Early delayed effects occur within a few weeks to six
months following RT and are reversible in most cases. Lethargy, somnolence, and resurgence of neurological signs, and
a transient decline in cognitive functioning may occur, but
these factors are not predictive of delayed cognitive deficits.
Transient white matter hyperintensity suggesting demyelination may be seen on magnetic resonance imaging (MRI),
and are thought to be related to BBB disruption or injury to
oligodendrocytes.

The late-delayed effects of RT become apparent a few
months to many years after treatment, and often produce
irreversible and progressive damage to the CNS (Sheline,
Wara, & Smith, 1980). Risk factors for developing delayed
RT-induced brain injury include greater volume of radiated tissue, higher total dose of RT (> 2 Gy dose per fraction), concomitant administration of chemotherapy, age
greater than 60 years, and presence of comorbid vascular
risk factors (Behin, 2003; Constine, Konski, Ekholm,
McDonald,  & Rubin, 1988; DeAngelis & Posner, 2009).
MRI typically shows hyperintensities in periventricular and
subcortical white matter, and these changes are often more
pronounced in older patients (see Figure 23.2). Radiationinduced microbleeds were recently described in patients with
gliomas treated with external-beam RT (Bian, Hess, Chang,
Nelson, & Lupo, 2013). In a diffusion tensor imaging (DTI)
study, there was evidence of early dose-dependent progressive
demyelination and axonal degeneration after RT, and subsequent diffuse dose-independent demyelination (Chapman
et al., 2013; Nagesh et al., 2008). Chapman et al. (2013) used
DTI to study 14 patients with brain metastases before and
after whole-brain RT ± chemotherapy. The results showed
regional variation in white matter changes post-RT, with a

significant decrease in fractional anisotropy in the cingulate
and fornix. A study using positron emission tomography
(PET) in a small cohort of brain tumor patients reported
dose-dependent reduction in glucose metabolism in brain
regions that received greater than 40 Gy at three- and sixmonth follow-ups; these changes correlated with decreased
performance on tests of problem solving and cognitive flexibility (Hahn et al., 2009).
A substantial number of brain tumor patients treated with
RT experience cognitive dysfunction that varies from mild
to severe, and it is currently considered the most frequent
complication among long-term survivors (Behin, 2003). The
peak of neurocognitive difficulties resulting from RT occurs

Figure 23.2

T1-weighted axial MRIs showing periventricular
white matter abnormalities in a 50-year-old man six
years post treatment with high-dose chemotherapy
and whole-brain radiotherapy


Cognitive Functions in Adults With Cancers
approximately six months to two years after treatment completion, and its incidence is proportional to the percentage
of patients with disease-free survival (DeAngelis, Yahalom,
Thaler, & Kher, 1992). The variability in the documented frequency of RT-induced cognitive deficits may be partially associated with the insensitivity of the methods of assessment used,
duration of follow-up, retrospective nature of many studies,
inclusion of patients treated with different regimens, and population discrepancies. In addition, the high incidence of tumor
recurrence and short-term survival in patients with high-grade
malignancies have often been considered confounding variables
that hampered the ability to quantify the frequency, onset, and
course of the delayed cognitive effects of RT (Crossen, Garwood, Glatstein, & Neuwelt, 1994). A review of the literature

suggests that the pattern of neuropsychological impairments
associated with the delayed effects of whole-brain RT is diffuse
(Duffey, Chari, Cartlidge, & Shaw, 1996), and most consistent
with frontal-subcortical dysfunction with deficits in attention,
executive functions, learning and retrieval of new information,
and graphomotor speed (Archibald et al., 1994; Crossen et al.,
1994; Salander, Karlsson, Bergenheim, & Henriksson, 1995;
Scheibel, Meyers, & Levin, 1996; Taphoorn & Klein, 2004;
Wefel, Kayl, et al., 2004; Weitzner & Meyers, 1997).
In recent years, conformal RT that includes the area of the
tumor and surrounding margin has supplanted whole-brain
RT in the treatment of gliomas due to equivalent efficacy and
reduced neurotoxicity (DeGroot, Aldape, & Colman, 2005).
Some studies suggest that conformal RT is associated with
less severe cognitive dysfunction than whole-brain RT (Torres
et al., 2003), but most studies were retrospective and revealed
variable outcomes ranging from no morbidity to marked
cognitive deficits (Armstrong et al., 2000; Armstrong et al.,
2002; Postma et al., 2002; Surma-aho et al., 2001; Taphoorn
et al., 1994). Recent research reported that radiation dose to
specific regions, such as the right temporal lobes and the hippocampi, may be more predictive of cognitive impairment
than total RT dose (Peiffer et al., 2013). Similarly, a prospective study of patients with low-grade or benign tumors treated
with fractionated stereotactic RT reported a dose-response
relationship, with higher RT doses to the hippocampi showing an association with impairment in word-list delayed recall
(Gondi, Hermann, Mehta, & Tome, 2013).
Chemotherapy Alone or Combined
WithRadiotherapy
The pathophysiological mechanisms of chemotherapyinduced CNS damage are not well understood. Candidate
mechanisms include demyelination, secondary inflammatory
response, oxidative stress, and DNA damage; immune dysregulation; and microvascular injury (Ahles & Saykin, 2007).

There is increasing evidence that chemotherapy has direct
toxic effects on progenitor cells, oligodendrocytes, white matter, gliogenesis, and neurogenesis (Dietrich, 2010). Increased
cell death and decreased cell division in the subventricular

563

zone and in the dentate gyrus of the hippocampus have been
reported in mice (Dietrich et al., 2006; Dietrich, Monje,
Wefel, & Meyers, 2008); neural progenitor cells and oligodendrocytes are particularly vulnerable.
Neurotoxicity has been reported after high-dose regimens
with procarbazine, lomustine, and vincristine (PCV) chemotherapy (Postma et al., 1998), and after high-dose methotrexate (HD-MTX) and high-dose cytarabine, particularly if RT
is administered before or during chemotherapy (DeAngelis &
Shapiro, 1991; see Figure 23.2). Chemotherapy administered
intrathecally is more likely to cause CNS toxicity than when
it is applied systemically. Combined treatment with RT and
chemotherapy may have a synergistic effect (Keime-Guibert,
Napolitano, & Delattre, 1998), as chemotherapy agents may
interfere with the same cellular structures as radiation and
may act as a radiosensitizer. Radiation may alter the distribution kinetics of chemotherapeutic agents in the CNS by
increasing the permeability of the BBB, affecting the ability of arachnoid granulations or choroid plexus to clear the
drug, or interrupting the ependymal barrier to allow drugs in
the cerebrospinal fluid to enter the white matter. Finally, RTinduced cellular changes may allow greater amounts of the
drug to enter nontumor cells or less of it to exit. The interactions between RT and HD-MTX are the most clearly demonstrated (Keime-Guibert et al., 1998), and nonenhancing,
confluent lesions in the periventricular and subcortical white
matter have been documented on MRI studies (Correa et al.,
2004; Keime-Guibert et al., 1998). Decrease in white matter
density in the corpus callosum, hippocampal cell death, and
memory impairments were reported in rats treated with HDMTX (Seigers et al., 2009). Carmustine, cyclophosphamide,
cisplatin, cytarabine, thiotepa, and methotrexate were found
to be associated with neurotoxicity, with changes in cortical

and subcortical brain regions (Rzeski et al., 2004). Deficits
in spatial and nonspatial memory have been described after
administration of methotrexate and 5-fluorouracil in mice
(Winocur, Vardy, Binns, Kerr, & Tannock, 2006). However,
the cognitive side-effects of chemotherapy are often difficult
to determine in brain tumor patients as most also receive RT
in the course of their treatment.
Variation in genetic polymorphisms may increase the
susceptibility to cognitive dysfunction following RT ± chemotherapy. In a recent cross-sectional study (Correa, et al.,
2013), brain tumor patients with at least one Apolipoprotein
E (APOE) є-4 allele had significantly lower scores in verbal
learning and delayed recall, and marginally significant lower
scores in executive function, in comparison to non-carriers
of a є-4 allele.
Neuropsychological Studies
High-Grade Tumors
Patients with high-grade gliomas often present with symptoms of increased intracranial pressure, seizures or focal


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Denise D. Correa and James C. Root

neurological signs (Greenberg et al., 1999). The majority of
patients undergo surgical tumor resection and receive a combined modality regimen of RT and chemotherapy; recent
trials involving glioblastoma patients have also included antiangiogenic therapy with bevacizumab (Gilbert et al., 2014).
The median survival time is less than two years for patients
with glioblastomas, and two to three years for anaplastic
astrocytomas (Carson, Grossman, Fisher, & Shaw, 2007;
Stupp et al., 2005). Cognitive impairment in patients with

high-grade gliomas is multifactorial and includes the tumor
and the adverse effects of treatment. Disease recurrence and
short-term survival have been considered confounding variables that limit the ability to quantify the frequency, onset,
and course of the delayed cognitive effects of RT and chemotherapy. Several studies have suggested that tumor progression contributes significantly to cognitive decline, and
that relatively stable performance is seen in patients without
recurrent disease (Brown et al., 2006).
Klein et al. (2001) studied cognitive functioning in 61
patients with high-grade gliomas following surgery or biopsy,
and included comparison groups of 50 patients with lung
cancer and age-matched healthy controls. As compared to
healthy controls, cognitive impairment (i.e., attention and
executive functions) was evident in all glioma patients and
52% of lung cancer patients. The use of antiepileptic medication was associated with working memory deficits. Patients
with tumors in the right hemisphere had greater difficulties in
visuospatial tests, and patients with left hemisphere tumors
showed greater susceptibility to interference and slower
visual scanning. Bosma et al. (2007) assessed cognitive functions at eight- and 16-month intervals after RT in 32 and 18
high-grade glioma patients, respectively. Patients with tumor
progression had a more pronounced cognitive decline (i.e.,
psychomotor speed, executive functions) than patients who
remained stable; however, the decline was also considered
to be in part related to the side effects of antiepileptics and
corticosteroids. However, in a recent study of patients with
high-grade tumors (de Groot et al., 2013) treated with levetiracetam (n = 35), valproic acid or phenytoin (n = 38), or no
antiepileptics (n = 44), there were no significant differences
on cognitive test performance between patients on newer
compared to older antiepileptics and patients receiving no
medication six weeks postsurgery; there was a beneficial
effect of both antiepileptics on verbal memory.
Hilverda et al. (2010) studied 13 patients with glioblastoma multiforme treated with RT and temozolomide with

no evidence of disease progression. Neurocognitive evaluations were performed after surgery, six weeks post-RT
and concomitant temozolomide, and after three cycles of
adjuvant temozolomide in progression-free patients. The
results showed that at baseline, 11 patients had impaired
attention, information processing speed, and executive
functions in comparison to healthy controls. At the first
follow-up, four patients improved, four deteriorated, and the
others were relatively stable. At the last follow-up, cognitive

performance remained stable in all domains for 11 patients,
with one patient improving and one patient declining in the
interim. The authors concluded that cognitive functions are
likely to be relatively stable in the absence of disease progression. Froklage and colleagues (2013) assessed cognitive
functions and radiological abnormalities in patients with
newly diagnosed high-grade gliomas treated with chemoradiation followed by adjuvant temozolomide. Neuropsychological assessments were conducted before treatment
and prior to adjuvant temozolomide (n = 33), during and
after temozolomide (n = 25 and 17, respectively), and three
and seven months post treatment completion (n = 9 and 5,
respectively); patient dropout was primarily due to disease
progression. In comparison to matched healthy controls,
63% of patients had deficits in executive functions, processing speed. and working memory at baseline. Approximately
70% of the patients remained stable during the follow-up
period, and most of the patients who declined had tumor
progression. Cerebral atrophy and white matter hyperintensities developed or worsened in approximately 45% of patients
during follow-up.
Brown et al. (2006) reported the results of prospective
Mini-Mental Status Examinations (MMSE) in 1, 244 highgrade tumor patients who participated in the North Central
Cancer Treatment Group treatment trials, which used radiation and nitrosurea-based chemotherapy. The proportion of
patients without tumor progression who had significant cognitive deterioration ranged from 13% to 18%, and remained
stable over the 24-month follow-up period; a decline in

MMSE scores was a predictor of more rapid time to tumor
progression and preceded radiographic changes. Corn et al.
(2009) examined QoL and mental status in 203 patients with
glioblastoma multiforme within the context of a Phase I/
II study of the RTOG to assess the impact of dose escalation conformal RT. Patients were administered the MMSE
at the start and at the end of radiation, and at four-month
intervals subsequently. The results showed a decline in the
MMSE over the follow-up period, and this was considered
to be at least in part related to RT. However, considering the
demonstrated low sensitivity of cognitive screening measures
(e.g., MMSE) to detect cognitive dysfunction in brain tumor
patients (Meyers & Wefel, 2003), the findings of these two
large studies may represent an underestimation.
A Phase II trial evaluated cognitive functioning in 167
patients with recurrent glioblastoma treated with bevacizumab-based therapy (Wefel et al., 2011). Patients with
objective response to treatment or progression free survival
greater than six months had stable median cognitive test
scores across the 24-month follow-up, but patients with evidence of progressive disease exhibited cognitive decline. In a
prospective study of newly diagnosed glioblastoma patients
treated with temozolomide, hypofractionated stereotactic
RT and bevacizumab, 37 patients underwent longitudinal
neuropsychological evaluations (Correa et al., 2011). Linear mixed model analyses showed a significant decline in


Cognitive Functions in Adults With Cancers
set-shifting and verbal learning (p < 0.05) from baseline to
the four-month follow-up, and performance remained stable
or improved slightly at subsequent intervals. Visuospatial
memory was stable at four months, but showed a trend
toward a decline at subsequent follow-ups. The decline in

executive functions and memory in the early phase of treatment was thought to be related to the acute effects of RT.
In a recent, large clinical trial for patients with newly diagnosed glioblastoma comparing the efficacy of standard
chemo-radiation, maintenance temozolomide, and placebo
or bevacizumab, cognitive evaluations were performed longitudinally in patients without disease progression (Gilbert
et al., 2014). The initial results suggested that patients randomized to bevacizumab, compared to placebo, experienced
greater decline over time in executive functions and information processing speed, suggesting either bevacizumab-related
neurotoxicity or unrecognized tumor progression. In a recent
study of long-term survivors of anaplastic oligodendrogliomas treated with RT versus RT and procarbazine, lomustine
and vincristine (Habets et al., 2014), a variable pattern of
cognitive impairment was seen in 75% of patients who were
progression free, regardless of initial treatment type.
Low-Grade Tumors
Low-grade gliomas are slow-growing infiltrative tumors most
common in young and middle-aged adults, and the majority
of patients present with seizures and headaches (Greenberg
et al., 1999). The median survival ranges from five to ten
years, and these tumors invariably progress to more aggressive high-grade gliomas (Shaw et al., 2002). Treatment interventions remain controversial regarding the optimal timing
of surgical intervention, RT, and chemotherapy (Cairncross,
2000; Kiebert et al., 1998; Shaw et al., 2002; Soffietti et al.,
2010). Several studies that documented cognitive dysfunction in low-grade glioma patients found that the tumor itself,
rather than RT, was the primary contributing factor (Laack
et al., 2003; Taphoorn et al., 1994; Torres et al., 2003). However, studies including long-term survivors reported that
both partial and whole-brain RT was associated with cognitive dysfunction several years after treatment completion
(Douw et al., 2009), and a decline in nonverbal memory was
evident in some studies. Tumor-related epilepsy and the side
effects of antiepileptic medications also contribute to cognitive dysfunction in these patients (Klein, 2012). Methodological problems including differences in the sensitivity of
the neuropsychological measures administered, retrospective
designs, and the inclusion of patients with high- and lowgrade tumors, and patients treated with partial and wholebrain RT (Imperato, Paleologos, & Vick, 1990; Kleinberg,
Wallner, & Malkin, 1993; Torres et al., 2003) may account
for some of the variability of the findings in the literature.

A recent report by the Response Assessment in NeuroOncology group (RANO), recommended that standardized
assessments of cognitive functions and QoL be incorporated

565

in clinical trials involving low-grade glioma patients (van
den Bent et al., 2011). The characterization of tumor- and
treatment-related cognitive dysfunction in patients with
low-grade tumors is particularly relevant given the relatively
prolonged survival and the controversy in the effectiveness
of early treatment.
A cross-sectional study assessed cognitive outcome in 195
low-grade glioma patients (104 treated with RT 1–22 years
prior to enrollment) compared to 100 low-grade hematological cancer patients, and 194 healthy controls (Taphoorn et al.,
1994). Glioma patients completed the cognitive evaluation
at a mean of six years after diagnosis, and obtained lower
test scores than the cancer control group on psychomotor
speed, visual memory, and executive functions. Although the
authors concluded that the tumor had the most detrimental
effects on cognition, decreased verbal and visual memory
was evident in patients who received RT in daily fractions
exceeding 2 Gy, and some of the cognitive test scores declined
over time only among those treated with RT. Antiepileptic
treatment was associated with more pronounced cognitive
dysfunction. A follow-up study (Douw et al., 2009) included
65 of these patients who underwent a neuropsychological
re-evaluation at a mean of 12 years (range 6–28 years) after
the initial assessment. Patients who received RT showed a
decline in attention, executive function, and information
processing speed, regardless of fraction dose. White matter

hyperintensities and cortical atrophy correlated with worse
cognitive test performance. Surma-aho et al.(2001) assessed
cognitive functioning in low-grade glioma patients approximately seven years post-RT ± chemotherapy (n = 28) or surgical resection alone (n = 23); 19 patients had whole-brain
RT and nine had focal RT. The results showed that patients
treated with RT had significantly lower scores in percent
retention of visual materials and estimated Performance IQ,
and more extensive periventricular white matter abnormalities on MRI, in comparison to patients who did not receive
RT. The authors concluded that RT increased the risk for
cognitive impairment and leukoencephalopathy in patients
with low-grade tumors.
Correa et al. (2007) studied cognitive functions in 40
patients with low-grade gliomas: 24 patients had surgery
only, and 16 had conformal RT ± chemotherapy. Patients
treated with RT ± chemotherapy had lower scores in attention and executive functions, psychomotor speed, verbal and
nonverbal memory, and naming than untreated patients.
In addition, patients who completed treatment at intervals
greater than three years had significantly lower scores in nonverbal memory. Antiepileptic polytherapy, treatment history,
and disease duration contributed to reduced psychomotor
speed; 62% of treated patients had white matter disease on
MRI, whereas only 10% of the untreated patients had such
changes. In a subsequent study (Correa et al., 2008), 25 of
these patients completed additional cognitive follow-ups.
The results showed a mild decline in nonverbal memory
12 months after the initial evaluation regardless of treatment


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Denise D. Correa and James C. Root

status; scores remained one standard deviation below normative values in other cognitive domains. Among the 16 patients
who completed a subsequent evaluation (12–27 months later),
there was improvement in untreated patients, but a decline in
some aspects of executive function in patients treated with RT
± chemotherapy. Disease duration and treatment history were
thought to contribute to the pattern of findings.
Armstrong et al. (2000) assessed cognitive functions
prospectively in 20 patients with low-grade tumors treated
with conformal RT. A decrement in verbal memory retrieval
was evident during the early delayed period following RT
with improvement at longer intervals. The long-term effects
of RT on cognition were examined in a subsequent study
involving 26 patients with low-grade tumors (Armstrong,
Stern, & Corn, 2001). A selective decline in learning and
recall of visual information five years post-RT was detected
despite continued improvement up to that point. Long-term
improvements were noted on tests of attention, executive
functions, and verbal recall. The authors concluded that
partial RT was not associated with significant delayed cognitive impairments in this population. In a recent study
(Gondi et al., 2013), 18 patients with low-grade or benign
tumors treated with fractionated stereotactic RT completed
a neuropsychological evaluation at baseline and 18 months
following treatment. The results suggested that RT dose
greater than 7.3 Gy to 40% of the bilateral hippocampi was
associated with impairment on a list-learning delayed recall
test. Alterations in functional connectivity using magnetoencephalography have also been described recently in patients
with low-grade gliomas (Bosma et al., 2008).
Primary Central Nervous System
Lymphoma (PCNSL)
PCNSL is a rare infiltrative tumor that develops most frequently in the subcortical periventricular white matter, with

single lesions occurring in 60%–70% of patients and multifocal lesions in 30%–40%. It is a disease of middle and late
adult life with a mean age at diagnosis of 60 years, and it is
slightly more common in men. Focal neurological signs are
the most common presentation followed by psychiatric symptoms, headaches, and seizures (Batchelor et al., 2012; Rubenstein, Ferreri, & Pittaluga, 2008). The standard treatment for
PCNSL often includes HD-MTX regimens and whole-brain
RT. Although this treatment approach is effective, with a
median survival of 30 to 60 months (DeAngelis et al., 2002),
it is associated with delayed neurotoxicity in most patients
(Correa et al., 2012; Poortmans et al., 2003; Thiel et al.,
2010). Delayed treatment-related cognitive dysfunction has
been recognized as a frequent complication among long-term
survivors, and may interfere with QoL (Correa et al., 2007).
Recent studies suggest that HD-MTX without RT can be
efficacious in the treatment of PCNSL and diminish the risk
for delayed neurotoxicity (Juergens et al., 2010; Rubenstein
et al., 2013; Thiel et al., 2010). However, since disease relapse

is relatively common and some patients require salvage
therapy, the optimal induction and consolidative therapy for
PCNSL remains controversial. The importance of assessing
the incidence and extent of cognitive dysfunction associated
with HD-MTX regimens with and without WBRT has been
recognized by the International Primary CNS Lymphoma
Collaborative Group (IPCG; (Abrey et al., 2005; Ferreri,
Zucca, Armitage, Cavalli, & Batchelor, 2013) and guidelines
for standardized cognitive assessments to be incorporated in
clinical trials have been developed (Correa et al., 2007). A
literature review indicated that cognitive function was evaluated systematically in a relatively limited number of studies,
and methodological problems limited the understanding of
the contribution of disease and treatments (Correa et al.,

2007).
RT AND CHEMOTHERAPY REGIMENS

Studies involving patients treated with whole-brain RT and
HD-MTX, or with whole-brain RT and chemotherapy with
BBB disruption reported significant cognitive impairment.
The pattern of cognitive deficits was diffuse and the domains
disrupted included attention and executive functions, psychomotor speed, and learning and retrieval of new information. Harder et al. (2004) studied cognitive functions in
19 PCNSL patients at a mean of 23 months after treatment
with HD-MTX followed by whole-brain RT. In comparison
to a non-CNS-cancer control group, PCNSL patients had
lower scores on verbal and nonverbal memory, attention,
executive function, and motor speed. Correa et al. (2012)
studied 50 PCNSL treated with whole-brain RT and HDMTX (n = 24), or HD-MTX alone (n = 26) between three and
54 months posttreatment. Patients treated with whole-brain
RT and HD-MTX had impairments in selective attention
and executive functions, verbal memory, and graphomotor speed across most cognitive domains; these were of
sufficient severity to interfere with QoL as more than 50%
were not working due to their illness. Patients treated with
HD-MTX alone had significantly higher scores on tests of
selective attention and memory than patients treated with
the combined modality regimen. Patients with more extensive white matter disease on MRIs had lower scores on tests
of set-shifting and memory. Thirty-three patients completed
an additional follow-up cognitive evaluation at a mean of
14–16 months after the initial visit. The results suggested
no significant changes on any of the cognitive tests among
patients treated with whole-brain RT and HD-MTX, but
patients who received HD-MTX alone obtained a significantly higher score on auditory attention. Doolittle, Korfel,
et al. (2013) studied neuropsychological functions and neuroimaging outcomes in 80patients with PCNSL evaluated at
a median of 5.5 years (range: 2 to 26 years) after diagnosis.

Treatment modalities included: HD-MTX (n = 32), HDMTX (intra-arterial) in conjunction with BBB disruption (n
= 25), HD-MTX followed by high-dose chemotherapy and


Cognitive Functions in Adults With Cancers
autologous stem cell transplant (ASCT) (n = 8), and HDMTX followed by whole-brain RT (n = 15); five of these
patients also received high-dose chemotherapy and ASCT
prior to whole-brain RT. Patients treated with HD-MTX
and whole-brain RT had significantly lower mean scores in
attention, executive function, and motor speed than patients
treated with HD-MTX in conjunction with BBB disruption,
and all patients treated without WBRT combined. Among
patients treated with BBB disruption chemotherapy, there
was a significant improvement in executive functions and no
evidence of decline in other domains (Doolittle, Dosa, et al.,
2013). White matter abnormalities were more extensive in
the patients treated with RT. The findings were consistent
with other studies, suggesting increased risk for delayed neurotoxicity following combined modality regimens. However,
the retrospective nature of these studies limited the ability
to examine the specific contributions of the tumor and the
delayed effects of treatment.
In a recent prospective study (Correa et al., 2009; Morris et
al., 2013), PCNSL patients treated with induction rituximab,
methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain RT (23.4
Gy) and cytarabine underwent cognitive evaluations prior to
treatment and up to four years after treatment completion.
At baseline, impairments in selective attention, memory, and
motor speed were evident. After induction chemotherapy,
there was a significant improvement in executive function
and memory. There was no evidence of significant cognitive

decline during the follow-up period, except for motor speed.
The preliminary findings were interpreted as evidence that
cognitive dysfunction was primarily related to the disease,
and that the new treatment approach with low-dose RT may
not be associated with progressive cognitive decline.
CHEMOTHERAPY REGIMENS

The studies that reported cognitive outcome in PCNSL
patients treated with HD-MTX alone or with BBB disruption chemotherapy without RT were mostly prospective
(Correa et al., 2007). Several studies documented cognitive
impairment prior to therapy in attention, executive functions,
memory, graphomotor speed, and language. Posttreatment
follow-up intervals were variable across studies, but several
reported either stable or improved cognitive performance.
Methodological problems in several of these studies, however, limited the ability to discern the specific contributions
of the disease and chemotherapy alone regimens to cognitive
dysfunction.
Pels et al. (2003) performed cognitive evaluations in 22
patients between four and 82 months after completion of
treatment with HD-MTX. There was no evidence of decline
in attention, verbal memory, visual memory, word fluency,
or visual-construction abilities in patients who had either a
partial or a complete response to treatment. Fliessbach et
al. (2005) assessed cognitive functions in 23 patients prior

567

to and up to a median of 44 months after treatment with
HD-MTX (all patients were in disease remission). At the
pretreatment baseline, impairments were evident in attention and executive functions, verbal and nonverbal memory,

and word fluency; these were classified as mild (z ≤ −1.5) in
three patients, moderate (z ≤ −2 and > −3) in ten, and severe
(z ≤ −3) in six patients. At the last follow-up, impairment
(in at least one domain) was mild in five patients, moderate in five, and severe in one; 12 patients had no deficits.
Twenty-one patients improved, but scores remained in the
low average range on tests of attention, non-verbal memory,
and word fluency. The authors concluded that the cognitive
deficits were associated primarily with tumor and there was
no treatment-related cognitive decline. The most sensitive
domains were attention, executive functions, and memory.
McAllister et al. (2000) studied a cohort of 23 prior to and
post BBB disruption chemotherapy (mean =16.5 months, SD
= 10.9). The results showed significantly improved cognitive
functioning posttreatment (summary z-score). When examining individual tests, there was evidence of improvement
in intellectual functioning, learning, memory, attention,
and visuospatial skills, with a nonsignificant trend demonstrated for executive functioning; seven patients had cognitive decline, mostly in motor speed. Neuwelt et al. (1991)
studied 15patients before and one year after BBB disruption
chemotherapy; nine patients were also seen for long-term
follow-up (mean of 3.5 years after diagnosis). Focus of data
analysis was on the summary z-score, which ranged at baseline from −2.59 to 0.46 with a mean of −1.1 (SD = 1.1). At
the end of treatment, the summary score ranged from −1.45
to 0.26 with a mean of 0.35 (SD = 0.52), suggesting a significant improvement in cognitive functioning from baseline.
As reported recently by Doolittle, Dosa, et al. (2013), longterm follow-up of PCNSL patients at a median of 12years
after BBB disruption chemotherapy indicated either stable
or improved cognitive functions.
Metastatic Brain Tumors
Brain metastases are common and develop most often in
patients with lung cancer (50%), followed by breast cancer
(15%–20%) and melanoma (10%), and less frequently in
other cancers (e.g., colorectal, kidney) (Lassman & DeAngelis, 2003). Patients may present with headaches, focal

weakness, altered mental status, and seizures. Standard
treatment has involved surgical resection and external beam
whole-brain RT; the median survival is four to six months
(Lassman & DeAngelis, 2003). Recent randomized trials
comparing stereotactic radiosurgery plus whole-brain RT
versus whole-brain RT alone reported improvement in survival with the addition of radiosurgery in patients with solitary metastases (Andrews et al., 2004; Ayoma et al., 2006).
Temozolomide and radiosensitizers have also been added to
the regimen recently (Abrey et al., 2001). Although wholebrain RT has been shown to improve tumor control across


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several studies (Brown, Asher, & Farace, 2008) and to reduce
the development of subsequent metastases (Kocher et al.,
2011), the neurotoxicity of whole-brain RT, including cognitive dysfunction, has been a concern. A recent report by
RANO supports the inclusion of standardized assessments
of cognitive functions and QoL in clinical trials involving
patients with brain metastases (Lin et al., 2013).
Deficits in memory and motor speed have been documented in patients with newly diagnosed or recurrent
metastases evaluated either during or after whole-brain RT
(Herman et al., 2003; Platta, Khuntia, Mehta, & Suh, 2010).
Several studies also documented cognitive dysfunction prior
to therapy, and Meyers et al. (2004) reported that baseline
cognitive performance predicted survival in patients with
brain metastases. A pilot study including 15 patients treated
with stereotactic radiosurgery alone (Chang et al., 2007) documented impaired executive function, manual dexterity, and
memory at baseline; 13 patients declined on one or more tests
at the one-month follow-up, and the five long-term survivors

had stable or improved cognitive performance. Welzel et al.
(2008) studied memory functions prospectively in 44 patients
treated with prophylactic RT for small-cell lung cancer and
in patients with brain metastases treated with whole-brain
RT. At baseline, lung cancer patients had lower memory
scores than patients with brain metastasis. Verbal memory
decline was evident during RT in patients with metastases
only, but at the eight-week post-RT follow-up both groups
had memory impairment.
Meyers et al. (2004) studied cognitive outcome in the context of a Phase II randomized trial involving 400 patients
with brain metastases treated with whole-brain RT alone
or in combination with motexafin gadolinium. At baseline,
91% of patients had impairment in one or more cognitive
domains, and 42% had impairment in four of eight tests.
Optimal tumor control following treatment correlated with
preservation of cognitive function, and in a small group of
long-term survivors there was stable or improved performance. In a Phase III trial involving 554 patients with brain
metastasis (Mehta et al., 2009), the interval to neurocognitive
decline was prolonged in the group treated with whole-brain
RT and motexafin gadolinium. Serial neurocognitive assessments were performed in the context of a randomized trial
involving patients with one to three brain metastases treated
with radiosurgery (n = 30) versus radiosurgery plus wholebrain-RT (n = 28) (Chang et al., 2009). Patients treated with
radiosurgery plus whole-brain RT were significantly more
likely to show a decline in verbal learning at four months
posttreatment than patients treated with radiosurgery alone.
In a study of 208 brain metastases patients treated with
whole-brain RT (30 Gy) (Li, Bentzen, Renschler, & Mehta,
2007), the median time to decline in executive and motor
functions was longer in patients with a poor response to treatment (i.e., less tumor shrinkage). In patients surviving more
than 15 months, reduced tumor size was correlated with preserved executive and motor functions, but not with memory

performance; a significant decline in memory at four months
posttreatment was noted. In addition, the risk of delayed
leukoencephalopathy was found to be significantly higher for
patients with brain metastases treated with radiosurgery and
whole-brain RT relative to patients who had radiosurgery
alone (Monaco et al., 2013). A recent review of randomized
controlled studies involving patients treated with prophylactic RT, radiosurgery, and radiosurgery and whole-brain
RT suggested that whole-brain RT, particularly high-dose
regimens (36 vs. 25 Gy), was associated with a deleterious
effect in memory, executive functions, and processing speed
(McDuff et al., 2013).
Preventive or Treatment Interventions
There are no established preventive or therapeutic interventions for cancer-treatment-related cognitive dysfunction.
Ghia et al. (2007) developed a hippocampal-sparing intensity-modulated approach to whole-brain RT that limits the
radiation dose to the hippocampus with the intent of reducing the neurocognitive sequelae of RT. Preliminary results
from a clinical trial involving 113 patients with brain metastases (Gondi et al., 2013) showed that sparing the subgranular zone of the hippocampus during whole-brain RT was
associated with more preserved memory function at the fourand six-month posttreatment follow-ups, in comparison to
historical controls treated with standard whole-brain RT;
however, only 28 patients were available for the six-month
assessment (Brown et al., 2013). In a randomized study, the
potential protective effects of memantine versus placebo on
cognitive function were evaluated in 508 patients with brain
metastases receiving whole-brain RT (Brown et al., 2013).
The results showed that patients treated with memantine had
significantly longer time to cognitive decline, and a reduced
rate of decline in memory, executive function, and processing speed compared to placebo; however, attrition may have
limited statistical power as only 29% of patients completed
the 24-week assessment.
Treatments that target the vascular mechanism of RT

damage including hyperbaric oxygenation, anticoagulation,
and aspirin have been attempted, but without clear benefits
(DeAngelis & Posner, 2009). There is preliminary evidence
suggesting that bevacizumab may reduce abnormal enhancement associated with necrosis, possibly through the removal
of VEGF-induced reactive vascularization (Torcuator et
al., 2009). In a placebo-controlled, randomized study of
bevacizumab for the treatment of RT necrosis in 14 brain
tumor patients (Levin et al., 2011), there was a decrease in
MRI enhancement and improvement in neurological symptoms in all patients treated with bevacizumab. A decrease in
radiation necrosis on MRI following bevacizumab was also
reported in 11 patients with brain metastases treated with
stereotactic radiosurgery (Boothe et al., 2013). However, a
recent review of the use of bevacizumab for the treatment of
RT necrosis suggested that although most studies reported


Cognitive Functions in Adults With Cancers
a reduction in radiographic volume of necrosis-associated
edema, a high rate of serious complications raised concerns
about this treatment approach (Lubelski, Abdullah, Weil, &
Marko, 2013).
Pharmacological treatments for RT-induced cognitive
dysfunction have been based primarily on therapies used for
other neurological disorders that cause similar symptoms
(Kim et al., 2008). Agents such as psychostimulants and acetylcholinesterase inhibitors have been used to treat cognitive
dysfunction in patients with brain tumors. Comprehensive
reviews of studies on interventions for this clinical population indicated that there are several completed and ongoing
trials using these and other medications, as well as cognitive
rehabilitation and behavioral interventions (Gehring, Aaronson, Taphoorn, & Sitskoorn, 2010; Wefel, Kayl, et al., 2004).
A prospective open-label Phase II study was conducted to

assess the efficacy of donepezil in the treatment of cognitive
dysfunction in 24 patients with primary brain tumors (Shaw
et al., 2006). After 24 weeks of treatment there was evidence
of improvement in attention, verbal and visual memory, in
mood, and QoL. A recent open-label randomized pilot study
examined the efficacy of four weeks of methylphenidate and
modafanil in 24 brain tumor patients either during or following treatment with RT or chemotherapy (Gehring et al.,
2012). The results showed a beneficial effect of stimulant
treatment in speed of processing and executive functions
requiring divided attention, and on patient-reported fatigue
and QoL, regardless of the medication used. However, the
results were interpreted with caution give the small sample
size and large proportion of dropouts. A recent multicenter
double-blind placebo-controlled study including 37 patients
with primary brain tumors treated with modafinil for six
weeks showed no beneficial effects on cognitive function,
fatigue, or mood in comparison to placebo (Boele et al.,
2013).
The small number of studies using cognitive rehabilitation in brain tumor patients suggests some beneficial effects,
but problems with accrual and attrition and methodological
problems limit the evaluation of its efficacy (Gehring et al.,
2010). In a study involving 13 brain tumor patients (Sherer,
Meyers, & Bergloff, 1997), there was a significant increase
in functional independence in approximately half of the
patients following three to 12 weeks of training in the use
of compensatory strategies. Locke et al. (2008) compared
the feasibility of memory and problem solving training in
dyads of primary brain tumor patients and caregivers versus a no-intervention control group. At the three-month
follow-up 50% of patients reported using the strategies,
but there was no significant intervention effect on QoL and

functional capacity and not enough patients completed the
neuropsychological assessment. Gehring et al. (2008) conducted a randomized controlled trial to assess the efficacy of
computer-based attention training and compensatory skills
training in 140 patients with gliomas; patients were randomly
assigned to the intervention group or to a wait list control

569

group. There was a significant improvement in self-reported
cognitive function but not on neuropsychological test performance immediately after completion of the seven-week
program. Conversely, at the six-month follow-up patients
showed an improvement in attention and verbal memory, but
not on self-reported cognitive function. The prevention of
cognitive deficits with agents that may protect neurons from
treatment-induced damage is an area of growing interest
(Kim et al., 2008), and the potential neuroprotective effects
of lithium and other agents are under investigation (Gehring
et al., 2010; Khasraw, Ashley, Wheeler, & Berk, 2012; Wefel,
Kayl, et al., 2004).

Non-CNS Cancers
Beyond the effects of primary CNS cancers on cognition,
non-CNS cancer diagnosis and treatment has also been
found to be associated with cognitive dysfunction. Among
primary cancers, breast cancer is relatively common, with
approximately 124 per 100,000 new cases diagnosed each
year, and a prevalence of approximately 2.8 million women
currently diagnosed in the United States alone (http://seer.
cancer.gov/statfacts/html/breast.html), with 89% survival
rates of five years or more. Given its prevalence and survival

rates, cognitive changes associated with breast cancer diagnosis and treatment have been most widely studied. In this
section we review cross-sectional and longitudinal studies
assessing neuropsychological outcome and self-reported cognitive dysfunction in individuals diagnosed with breast cancer. Contributions of structural and functional imaging that
may help to clarify the underlying changes in brain structure
and function following treatment are then discussed, followed by potential mechanisms by which treatments may
exert an effect on the brain and cognition.
While terms such as chemo-brain and chemo-fog would
indicate a primary role for chemotherapy, recent research
has questioned whether chemotherapy exposure alone is
either necessary or sufficient for cognitive decline following treatment (Hurria, Somlo, & Ahles, 2007). Treatment
varies with stage of disease but includes surgical resection
potentially in combination with radiation treatment to the
breast, adjuvant chemotherapy in later stages, and endocrine
therapies depending on receptor characteristics of tumor
cells. Surgical resection alone (lumpectomy or mastectomy)
may be performed in early stage disease in cases in which the
tumor is relatively small and there is no evidence of extended
disease either to the lymph nodes or other anatomical sites.
Adjuvant chemotherapy treatment, in which chemotherapy
drugs are delivered following surgical resection, may be used
to prevent recurrence or in cases in which the disease is found
to extend, i.e., to have metastasized, beyond the primary site.
Radiation may be used to reduce the size of a tumor prior to
resection, and to prevent recurrence following resection, as
well as in later stages of the disease. Hormonal therapies may
be used following primary treatment on an extended basis


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Denise D. Correa and James C. Root

in cases in which tumor cells are found to have a high receptor count for either progesterone or estrogen; these therapies
work by reducing availability of estrogen and so lower the
promotion of tumor cells.
Self-Reported Cognitive Changes
Following Treatment
Changes in cognitive function following treatment, including slowing, inattention, distraction, forgetfulness, difficulties in multitasking, and language function, are commonly
reported by cancer survivors. Early research found that
approximately half of cancer patients reported some change
in cognition at one point in their treatment (Cull, Stewart, &
Altman, 1995). Six or more months following treatment,
30% of lymphoma patients reported concentration difficulties and 52% reported forgetfulness (Cull et al., 1996).
Schagen et al. (1999) described persistent self-reported
difficulties in concentration (31%) and memory (21%) in
breast cancer survivors at longer intervals. Ahles et al.
(2002) described self-reported difficulties in concentration
and complex attention in survivors of breast cancer and
lymphoma up to ten years after chemotherapy. Incidence
of self-reported cognitive dysfunction at similar intervals
was found in other studies surveying the effects of treatment of diverse cancers on cognition (Castellon et al., 2004;
Downie, Mar Fan, Houede-Tchen, Yi, & Tannock, 2006;
Hermelink et al., 2007; Jansen, Dodd, Miaskowski, Dowling, & Kramer, 2008; Mehnert et al., 2007; Poppelreuter
et al., 2004; Schagen et al., 2008; Shilling & Jenkins, 2007;
van Dam et al., 1998).
Cross-Sectional Neuropsychological
Studies—Posttreatment
The first studies to examine cognitive effects of treatment
were generally cross-sectional, comparing cancer patients
and healthy control groups, or comparing cancer patients

stratified by treatment regimen. In an early study comparing high-dose chemotherapy, low-dose chemotherapy, and
healthy control groups two years after completion of treatment, individuals treated with high-dose chemotherapy
performed significantly worse in measures of attention,
psychomotor speed, visual memory, and motor function
than healthy controls, while the high-dose group performed
significantly worse than the low-dose group only on a measure of reaction time (van Dam et al., 1998). In a study
examining breast cancer survivors approximately two years
following completion of cyclophosphamide, methotrexate,
and 5-fluorouracil (CMF) chemotherapy treatment compared with survivors treated with surgery and radiation
only, significantly greater impairment was found in the
chemotherapy group in domains of psychomotor speed,
motor function, attention, mental flexibility, and visual
memory (Schagen et al., 1999). Evidence for cognitive

effects at longer intervals was found by Ahles et al. (2002)
at approximately five years postdiagnosis, between chemotherapy and no-chemotherapy groups in the domains of
verbal memory and psychomotor speed. While other studies found similar differences between treatment groups and
healthy controls (Yamada, Denburg, Beglinger, & Schultz,
2010), a subset found significant differences only between
cancer-diagnosed (regardless of treatment) and healthy
control groups or normative data (Jim et al., 2009; Scherwath et al., 2006), while a minority failed to find any difference between treatments or health status (Donovan et al.,
2005; Inagaki et al., 2007; Yoshikawa et al., 2005). The most
recent and largest study (N = 196) of long-term effects of
chemotherapy exposure (mean = 20 years) found significantly lower performance on measures of immediate and
delayed verbal memory, psychomotor speed, and executive
functioning in chemotherapy-treated subjects compared to
healthy controls (Koppelmans et al., 2012).
The interpretation of these crosssectional studies and later
ones is limited due to the absence of a pretreatment, baseline time point. This is a significant limitation since work
following initial cross-sectional studies suggests that significant cognitive differences exist prior to treatment. Wefel

et al. (2004) found that 35% of women exhibited cognitive
impairment prior to cancer treatment, specifically in verbal
learning (18%) and memory function (25%). Ahles et al.
(2008) investigated pretreatment cognitive ability in healthy
controls, and patients diagnosed with invasive (Stages 1–3)
and noninvasive (Stage 0) breast cancer, and found significantly slowed reaction time in the invasive group compared
to healthy controls, and lower overall performance in the
invasive group compared to the healthy and noninvasive
patient groups. While pretreatment, baseline differences
remain poorly understood in regard to mechanism or etiology, that differences are present prior to treatment between
groups requires that longitudinal assessments be conducted
to delineate specific treatment-related contributions to cognitive dysfunction.
Longitudinal Neuropsychological Studies:
Pre- and Posttreatment
Given the potential for pretreatment cognitive dysfunction,
longitudinal studies generally find more modest declines in
cognitive dysfunction than cross-sectional, posttreatment
studies have reported. These studies have generally found
that a subset of patients are affected following treatment
within a larger cohort of unaffected individuals; as a result,
rates of impairment or decline are more useful in assessing
putative effects of treatment than reliance on group mean
differences, since group means will tend to obscure subgroup
differences. Also problematic are widely varying assessment
batteries and screening instruments, making aggregation of
numerous studies in systematic reviews or meta-analyses
difficult. Despite these issues, available data do suggest


Cognitive Functions in Adults With Cancers

significant treatment related effects found in longitudinal
studies, although a subset of studies have reported null
results.
In an early longitudinal study using published normative data for comparison, Wefel et al. (2004) found that
61% of chemotherapy treated patients exhibited a decline
in one or more cognitive domains, mainly consisting of
psychomotor speed, attention, and learning three weeks
following completion of treatment. Shilling, Jenkins, Morris, Deutsch, and Bloomfield (2005) found significant reliable change (declines on at least two or more measures)
from pretreatment baseline to six months posttreatment
compared to healthy controls in 34% of patients (18.6% in
healthy controls); they also found significant declines (time
X group interactions) in the patient group as compared to
controls were found in selective attention, working memory,
and delayed verbal memory measures. Schagen et al. (2006)
found a greater proportion of high-dose chemotherapy
patients declined from baseline to six-months posttreatment
time points (25%) compared with healthy control subjects
(6.7%), while standard-dose and cancer-diagnosed subjects
not treated with chemotherapy did not exhibit any significant difference. Stewart et al. (2008) found a greater proportion of chemotherapy-treated patients exhibited a reliable
decline (31%) than patients not treated with chemotherapy
(12%) with working memory the most affected. Collins
et al. (2009) found significant declines in working memory
and visual memory for chemotherapy treated patients
from baseline to six months posttreatment compared to
patients treated with hormonal therapies. Quesnel, Savard,
and Ivers (2009) compared groups treated with combination chemotherapy/RT to RT alone and to healthy controls
before and after treatment, and three months posttreatment; significant pretreatment attentional differences were
noted in the patient group compared to healthy controls,
with significant posttreatment verbal memory declines in
both patient groups and significantly greater verbal fluency

decline in the chemotherapy treated group. Vearncombe
et al. (2009) compared groups treated with chemotherapy
with or without hormonal and RT to a group not treated
with adjuvant therapies at baseline and four weeks following completion of treatment: 16.9% of the chemotherapy
group exhibited decline in verbal learning and memory,
abstract reasoning, and motor function following treatment, with an association of decreased hemoglobin and
increased anxiety to impairment.
Ahles et al. (2010) compared performance of patients
treated with chemotherapy, patients not treated with chemotherapy, and healthy controls at baseline, one month,
and six months following treatment. The chemotherapy
group failed to improve in verbal ability at the one-month
time point compared to the other groups, and a significant contribution of age and baseline cognitive reserve to
chemotherapy-related cognitive decline in processing speed
was found; performance in the chemotherapy group was

571

similar to no-chemotherapy and healthy controls at the
six-month time point. Wefel et al. (2010) examined performance in a single group of chemotherapy-treated patients
at pretreatment, during treatment, and approximately one
month following completion of treatment: 21% exhibited
dysfunction predominantly in learning and memory, executive function, and psychomotor speed at the pretreatment
time point; 65% of patients exhibited significant decline
in the same domains during or shortly after treatment
compared to baseline. Hedayati, Alinaghizadeh, Schedin,
Nyman, and Albertsson (2012) compared chemotherapy,
hormone therapy, no therapy, and healthy controls prior to
surgery, prior to adjuvant treatment, six months after start
of adjuvant treatment, and three months after completion
of treatment; results indicated significantly worse memory

performance for breast cancer diagnosed subjects regardless of treatment, and lower memory and processing speed
performance following chemotherapy treatment compared
with the pretreatment time point. Jansen, Cooper, Dodd,
and Miaskowski (2011) examined cognitive changes in
patients treated with doxorubicin and cyclophosphamide
combination (referred to as AC) therapy alone and AC
therapy followed by taxane before treatment, one week
and six months following completion of treatment. Prior
to therapy, 23% of patients exhibited cognitive impairment
with significant declines in visuospatial ability, attention,
and delayed memory immediately following treatment, and
general improvement after six months. Biglia et al. (2012)
examined cognitive functioning in a single group of women
diagnosed with breast cancer before and immediately after
completion of chemotherapy treatment, and reported a
significant decline in attention. Collins, Mackenzie, Tasca,
Scherling, and Smith (2013b) compared chemotherapy and
healthy control groups shortly after completion of treatment
and one year following completion of treatment: Results
suggested significantly improved global cognition performance at one year with a specific improvement in working memory; however, approximately one-third of patients
exhibited persistent cognitive dysfunction at the one-year
time point. In a novel study examining dose-response in
chemotherapy treatment, Collins, MacKenzie, Tasca,
Scherling, and Smith (2013a) conducted serial assessments
in women undergoing active treatment with chemotherapy
and compared these to seven yoked time points in a healthy
control group; declines in global cognitive performance as
well as specific declines in working memory, psychomotor
speed, verbal and visual memory performance were exhibited with increasing frequency over the seven assessment
points (chemotherapy group impairment time 1 = 11.7%

and at time 7 = 37%; control group impairment time 1 =
10% and at time 7 = 15.2%).
Other studies examining cognitive abilities at short intervals following treatment have failed to find significant effects.
Jenkins et al. (2006) found no significant differences between
groups treated with chemotherapy, endocrine/RT, and


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Denise D. Correa and James C. Root

healthy controls from pretreatment baseline to six months
posttreatment, but did find a potential effect of treatmentrelated menopause initiation on attention and memory
measures. Hermelink et al. (2007) assessed a single group of
patients before and toward the end of active treatment and
found mean performance before treatment to be significantly
below normative values in five out of 12 neuropsychological measures. At the second time point, approximately equal
proportions of patients exhibited reliable improvement (28%)
or decline (27%) from pretreatment performance, although
interpretation is limited given that no control group was
available for comparison. Mehlsen, Pedersen, Jensen, and
Zachariae (2009) compared patients treated with chemotherapy, cardiac patients, and healthy controls, but failed to
find any increased rate of impairment or decline in the chemotherapy group. Debess, Riis, Pedersen, and Ewertz (2009)
compared chemotherapy, chemotherapy and hormonal therapy, no-chemotherapy, and healthy control groups and found
no significant differences six months following completion
of treatment in any cognitive domain. Tager et al. (2010)
compared chemotherapy and no-chemotherapy groups at
baseline and at six months and one year following treatment;
while no significant cognitive effect was exhibited, women
not treated with chemotherapy improved in motor functioning compared to those treated with chemotherapy, which was

interpreted as being potentially related to improvement in
treatment-related peripheral neuropathy.
Several studies have examined longer-term cognitive effects
of treatment at one-year time points and beyond. At one
year posttreatment, Wefel et al. (2004) found improvement in
approximately 50% of affected patients, and persistent dysfunction was evident in the remaining half of the sample.
In a study with baseline assessment during active treatment,
one-year, and two-year time points, Mar Fan et al. (2008)
found 16% of patients on active treatment exhibited moderate to severe impairment on the High Sensitivity Cognitive
Screen (compared with 5% in the healthy control group).
These effects appeared to decline in severity at one- and twoyear time points, with 4.4% exhibiting moderate to severe
dysfunction in the chemotherapy group at one year (3.6% in
healthy controls), and 3.8% at two years (0% in healthy controls), although significant practice effects for this screening
measure are implicated. In a single group of chemotherapytreated patients using normative data as comparison, Wefel
et al. (2010) found that 61% of patients exhibited either new
or persistent decline at one year posttreatment with most frequent decline in learning and memory. In contrast, in a study
with pretreatment, six-month, and one-year time points, Collins et al. (2009) found no difference in impairment in chemotherapy-treated and hormone-treated patients (11% and
10% respectively) at one year, although, significantly, those
patients treated with chemotherapy and on active hormonal
treatments at one year exhibited decreased psychomotor
speed and verbal memory. Similarly, Ahles et al. (2010) found
no significant difference in performance for chemotherapy,

no-chemotherapy, and healthy control groups at one year
following treatment.
Summary of Neuropsychological Findings
Based on the literature reviewed, cognitive dysfunction following diagnosis and treatment of breast cancer is a significant concern in the immediate to intermediate periods
following active treatment, with a subset of studies finding
persistent cognitive dysfunction at one year and greater
time points, and even at 20 years posttreatment. Contextualization of these findings is important as several factors

influence interpretation of these results. First, estimates of
self-reported dysfunction would suggest much higher rates
of cognitive difficulties (up to 50%) than are found in either
cross-sectional or longitudinal studies employing objective
measures. Disagreement between self-report and objective
assessment is a well-known and typical finding in several
other neurocognitive syndromes (Reid & Maclullich, 2006).
Sources of disagreement that lead to overestimates of cognitive dysfunction include emotional factors that lead to negative perceptions of functioning, and priming as a result of
knowledge of potential effects of treatment (Schagen, Das, &
van Dam, 2009). Factors that potentially lead to underestimates of cognitive dysfunction following treatment include
insensitivity of objective measures to subtle cognitive dysfunction, assessment of performance in the rarefied environment of the consulting office that limits distraction and
competing demands, and potentially poor ecological validity of objective measures resulting in poor approximation of
real-world cognitive demands.
Second, cross-sectional objective studies would also suggest higher rates of cognitive dysfunction than similar longitudinal studies. As discussed in the previous section, this
may be due to preexisting cognitive dysfunction in patients
prior to treatment as has been found in a subset of studies.
It is important to note that “pretreatment” in this case is
before adjuvant chemotherapy treatment but not necessarily
before surgical resection. In the study by Ahles et al. (2008),
all patients were postsurgery at baseline, and in Wefel et al.
(2004) 50% of patients had already undergone either lumpectomy or mastectomy at baseline. Underscoring the importance of this observation, Wefel et al. reported that patients
who underwent surgical resection were approximately twice
as likely to have cognitive impairment compared to biopsy
alone (p = 0.03), although this did not meet the a priori significance level specified by the authors (p = 0.01). Another
potential influence on cognitive function prior to chemotherapy treatment is the stress related to cancer diagnosis and
treatment. In general, in those studies that formally assessed
mood symptoms, cognitive performance was not associated
with self-reported anxiety, although direct effects of chronic
stress and hypothalamic-pituitary-adrenal axis (HPA) dysregulation may be one promising future research direction
that so far had been only minimally studied. Regardless of

Cognitive Functions in Adults With Cancers
etiology, effects of other variables—e.g., stress of diagnosis
and treatment, surgical stress and potential inflammatory
dysregulation, and anesthetic exposure, all of which precede
chemotherapy treatment—may play a role in addition to specific effects of adjuvant therapies that follow.
Finally, longitudinal studies suggest that cognitive dysfunction following treatment may be subtle and exhibited in only
a subset of patients. Several potential mechanisms and risk
factors for posttreatment cognitive dysfunction have been
proposed (Ahles, Root, & Ryan, 2012; Ahles & Saykin, 2007)
that may predispose individuals to decline. Age and cognitive
reserve have been found to be associated with significantly
greater declines in processing speed from pre- to posttreatment in older individuals with lower cognitive reserve (Ahles
et al., 2010). Genetic contributions have also been identified,
including interaction of the COMT-Val (Val+; Val/Val; Val/
Met) genotype with treatment regimen on cognition (Small
et al., 2011), as well as the APOE-e4 genotype (Ahles et al.,
2003). To the extent that diagnosis and treatment may interact with specific risk factors prior to treatment, averaging
cognitive test performance within a given treatment group
may obscure significant patient subgroups in whom risk for
cognitive dysfunction may be heightened. In addition to
clarifying the longitudinal course of cognitive dysfunction
in survivors following treatment, potential mechanisms of
cognitive dysfunction have received increasing attention.
Principal among these has been research investigating underlying brain structure and function and potential changes due
to cancer diagnosis and treatment.
Structural and Functional Imaging Studies
Imaging studies investigating potential effects of cancer and
treatment on brain structure and function have accumulated

in recent years, and multiple reviews are available summarizing these findings (Ahles et al., 2012; de Ruiter & Schagen,
2013; Deprez, Billiet, Sunaert, & Leemans, 2013; McDonald &
Saykin, 2013; Reuter-Lorenz & Cimprich, 2013; see also
Tables 23.1 and 23.2). Following a similar trajectory as in
neuropsychological studies, early structural and functional
research focused on cross-sectional designs posttreatment,
limiting the interpretability of results given no pretreatment
baseline comparisons. Cross-sectional, posttreatment studies
using MRI (Abraham et al., 2008; Dale, Fischl, & Sereno,
1999; de Ruiter, Reneman, Boogerd, Veltman, Caan, et al.,
2011; Deprez et al., 2011; Inagaki et al., 2007) have documented reductions in gray matter, primarily in frontal cortex
and the hippocampus, and white matter integrity in cancer
survivors treated with chemotherapy, although negative
results have also been reported. In the most recent study utilizing DTI methods, while no group difference was reported,
significant associations of white matter integrity with time
since treatment were found within a breast cancer cohort at
mean interval of 20 years since treatment (Koppelmans
et al., 2014).

573

Longitudinal studies have reported similar results: First,
decreased gray matter density in bilateral frontal, temporal
(including hippocampus), and cerebellar regions and right
thalamus at one month postchemotherapy, with only partial
recovery at one year postchemotherapy in several structures,
compared with no significant changes in gray matter over
time in the no-chemotherapy cancer group or the healthy
controls (McDonald et al., 2010); and second, decreased
frontal, parietal, and occipital white matter integrity in

chemotherapy-exposed patients, with no changes in the
no-chemotherapy group or healthy controls posttreatment
(Deprez et al., 2012). Gray matter density alterations were
replicated by McDonald, Conroy, Smith, West, and Saykin
(2013), who found reduced gray matter density one month
after completion of treatment, which was associated with
greater self-reported executive dysfunction.
Cross-sectional studies of cancer survivors using functional imaging techniques, including functional MRI (fMRI)
(de Ruiter, Reneman, Boogerd, Veltman, van Dam, et al.,
2011; Ferguson, McDonald, Saykin, & Ahles, 2007; Kesler
et al., 2009; Kesler et al., 2011) and functional positron emission tomography (fPET) (Silverman et al., 2007), have demonstrated areas of increased and decreased activation during
performance, primarily in working memory and executive
functioning tasks, in survivors exposed to chemotherapy, as
compared with controls, in areas similar to the structural
differences described. McDonald et al. (2012) conducted a
longitudinal study using fMRI and found frontal lobe hyperactivation to support a working memory task before treatment, decreased activation one month postchemotherapy,
and a return to pretreatment hyperactivation at one year
posttreatment. Interestingly, two other studies reported
hyperactivation during a memory task before treatment in
patients with cancer compared with healthy controls, consistent with the reports of neuropsychological deficits at pretreatment (Cimprich et al., 2010; Scherling et al., 2011). One
interpretation is that pretreatment hyperactivation represents
an attempt to compensate for preexisting deficits; however,
over years, patients lose the ability for compensatory activation as a result of exposure to cancer treatments and/or ageassociated changes in the brain. More recent work has found
associations of functional recruitment with verbal working
memory (Lopez Zunini et al., 2013). In a novel pilot-study,
reductions in functional connectivity shortly after treatment
were found in the dorsal attention network and default mode
network, with partial resolution in the dorsal attention network at one year but persistent reduced connectivity in the
default mode network (Dumas et al., 2013).
The most recent imaging work has investigated putative

mechanisms of structural and functional alterations following treatment. A potential role of proinflammatory cytokines
is suggested by recent work finding an association of inflammatory biomarkers (IL-1ra; sTNF-RI) with regional brain
metabolism (Pomykala et al., 2013) utilizing fPET. Similarly,
hippocampal volumes and verbal memory performance have


574

Denise D. Correa and James C. Root

Table 23.1

Structural imaging studies

Authors

Design/
Modality

Assessment
schedule

Participants

Outcomes

Yoshikawa et al.
(2005)

Cross-sectional

MRI

t1: 12 months
post-tx

CTX+: n = 44
CTX−: n = 31

Inagaki et al. (2007)

Cross-sectional
MRI

t1: > 12 months
post-tx

Inagaki et al. (2007)

Cross-sectional
MRI

t1: > 36 months
post-tx

Abraham et al.
(2008)

Cross-sectional
DTI

t1: 22 months
post-tx

CTX+: n = 51
CTX−: n = 54
HC: n =55
CTX+: n = 73
CTX−: n = 59
HC: n =37
CTX+: n = 10
HC: n =9

No difference in hippocampal volume or memory
performance between CTX+ and CTX− at 12 months
posttreatment.
Smaller gray and white matter in prefrontal, parahippocampal,
cingulate, and precuneus in CTX+ compared to CTX− at
12 months posttreatment.
No difference between CTX+ and CTX− at 36 months
posttreatment.

McDonald, Conroy,
Ahles, West, and
Saykin (2010)

Longitudinal
MRI

t1: pre-tx
t2: one month

post-tx
t3: 12 months
post-tx

CTX+: n = 17
CTX−: n = 12
HC: n = 18

Koppelmans et al.
(2011)

Cross-sectional
MRI

t1: 21 years
post-tx

CTX+: n = 184
HC: n = 368

Deprez et al. (2011)

Cross-sectional
MRI
DTI
Longitudinal
MRI,
DTI
Cross-sectional
MRI, DTI,

MRS

t1: 80–160 days
post-tx
t1: pre-tx
t2: 3–4 months
post-tx
t1: > 9 years
post-tx

CTX+ n = 18
CTX− n = 10
HC n = 18
CTX+ n =34
CTX− n =16
HC n =19
CTX+: n = 17
CTX−: n = 15

McDonald et al.
(2013)

Longitudinal
MRI

Kesler et al. (2013)

Cross-sectional
MRI

t1: pre-tx
t2: 1 month
post-tx
t1: average 5
years post-tx

CTX+ n = 27
CTX− n = 28
HC n =24
CTX+ n = 42
HC n = 35

Conroy et al. (2013)

Cross-sectional
MRI

t1: average 6
years post-tx

CTX+ n = 24
HC n = 23

Koppelmans et al.
(2014)

Cross sectional
DTI

t1: average 20

years post-tx

CTX+ n = 187
HC n = 374

Deprez et al. (2012)

de Ruiter and
Schagen (2013)

Lower FA in genu and slower processing speed in
CTX+ compared with healthy controls at 22 months
posttreatment.
Decreased gray matter density in both CTX+ and
CTX− compared with healthy controls at one month
posttreatment. Decreased frontal, temporal, thalamic,
and cerebellar gray matter density in CTX+ at one month
posttreatment compared with pretreatment. Gray matter
density recovered in the CTX+ group with areas of reduced
density remaining at one year posttreatment.
Smaller total brain volume and gray matter volume
in CTX+ compared with health controls at 21 years
posttreatment.
Decreased frontal and temporal FA and increased frontal
MD in CTX+ compared to CTX− and healthy controls
80–160 days posttreatment.
Decreased frontal, parietal, and occipital FA in CTX+ with
no changes in either CTX− or healthy controls at three to
four months —posttreatment.
Reduced white matter integrity in CTX+ compared

with CTX− > 9 years −posttreatment. Reduced N−
acetylasparate/creatine in left centrum semiovale in CTX+
compared with CTX− > 9 years −posttreatment. Smaller
posterior parietal volume in CTX+ compared with CTX− >
9 years —posttreatment
Reduced gray matter density in the chemotherapy treated
group at one month post-completion of treatment.
Left hippocampal volume reduced in chemotherapy treated
group. IL-6 and TNFa increased in chemotherapy group.
Hippocampal volume positively correlated with TNFa and
negatively correlated with IL-6.
CTX+ group exhibited regional reductions in gray matter
density compared to HC. Time since treatment was
associated with greater gray matter density in CTX+ group.
Oxidative DNA damage was negatively correlated with gray
matter density.
No significant difference in global or regional white matter
integrity. Time since treatment was associated with declining
white matter integrity.

Notes: CTX+ = chemotherapy; CTX− = no chemotherapy; MRS = magnetic resonance spectroscopy; HC = healthy controls; FA = fractional anisotropy;
MD = mean diffusivity


Cognitive Functions in Adults With Cancers
Table 23.2

575

Functional imaging studies

Authors
Pretreatment
Cimprich et al.
(2010)

Design/
Modality

Crosssectional
fMRI
Scherling, Collins, CrossMackenzie,
sectional
Bielajew, and
fMRI
Smith (2011)
Posttreatment
Ferguson et al.
(2007)

Assessment
Schedule

Participants

In-Scanner Task

Outcomes

t1: pre-tx

only

BC: n = 10
HC: n = 9

Verbal working
memory

t1: pre-tx
only

BC: n = 23
HC: n = 23

Visual N-back

Greater bilateral activation during verbal working
memory task in breast cancer diagnosed subjects
compared to healthy controls pretreatment.
Greater inferior frontal gyrus, insula, thalamus and
midbrain activations during working memory task
in breast cancer diagnosed subjects compared with
healthy controls pretreatment.

Crosst1: 22
sectional
months
MRI; fMRI post-tx

CTX+: n = 1

HC: n = 1

Auditory N-back Greater WM hyperintensities and greater spatial
extent of frontal activation during working memory
in the CTX+ case compared with twin healthy
control case.
Silverman et al.
Crosst1: 5–10
CTX+: n = 5
Paired word
Lower inferior frontal gyrus metabolism in CTX+
(2007)
sectional
years post-tx CTX+Tam: n =7 memory task
compared to CTX- and healthy controls 5to 10years
PET
CTX−: n = 5
10-minute delay, posttreatment. Lower basal ganglia metabolism
HC: n = 3
1-day delay
in CTX+Tam treated subjects compared to
CTX+, CTX−, and healthy controls 5to 10years
posttreatment.
Kesler, Bennett, Crosst1: 3 years
CTX+: n = 14
Verbal declarative Lower prefrontal cortex activation during encoding
Mahaffey, and
sectional
post-tx
HC: n = 14

encoding
in CTX+ compared to healthy controls 3years
Spiegel (2009)
fMRI
Verbal declarative posttreatment. Greater regional activations during
recognition
recall in CTX+ compared to healthy controls 3years
posttreatment.
Card sorting task Lower left middle dorsolateral prefrontal cortex
Kesler, Kent, and Crosst1: 5 years
CTX+: n = 25
activation and premotor cortex activation in breast
post-tx
CTX−: n = 19
O’Hara (2011)
sectional
cancer diagnosed subjects compared to healthy
fMRI
controls. Lower left caudal lateral prefrontal cortex
activation in CTX+ compared with CTX− and
healthy controls 5years posttreatment.
de Ruiter et al.
Crosst1: 10 years CTX+: n = 19
Tower of London, Lower dorsolateral prefrontal cortex activity during
(2011)
sectional
post-tx
CTX−: n = 15
Paired Associates Tower of London task, lower parahippocampal
fMRI

gyrus activity during paired associates task in
CTX+ compared to CTX− 10 years posttreatment.
McDonald et al. Longitudinal t1: pre-tx
CTX+: n = 16
N-Back Task
Greater frontal activation and lower parietal
(2012)
fMRI
t2: 1 month CTX−: n = 12
activation at baseline in BC diagnosed patients
post-tx
HC: n = 15
relative to controls. Lower frontal activation in
t3: 1 year
BC-diagnosed patients relative to healthy controls
post-tx
immediately following treatment. Greater frontal
activation in BC diagnosed patients relative to
healthy controls one year following treatment.
Lopez Zunini
Longitudinal t1: pre-tx
CTX+: n =21
Verbal recall task At pre-tx, CTX+ exhibited reduced recruitment in
et al. (2013)
fMRI
t2: 1 month HC: n = 21
anterior cingulated compared to controls. At one
post-tx
month post-tx, CTX+ exhibited reduced recruitment
in bilateral insula, left inferior orbitofrontal cortex

and left middle temporal gyrus compared to controls.
Fatigue, depression, and anxiety were associated with
a subset of difference in recruitment.
Dumas et al.
Longitudinal T1: pre-tx
CTX+ n =9
Resting state
Reductions in functional connectivity shortly after
(2013)
fMRI
T2: 1 month
functional
treatment were found in the dorsal attention network
post-tx
connectivity
and default mode network, with partial resolution in
T3: 1 year
the dorsal attention network at one year but persistent
post-tx
reduced connectivity in the default mode network.
Resting FDG
Association of inflammatory biomarkers (IL-1ra;
Pomykala et al.
Longitudinal T1: post-tx CTX+ n = 23
CTX− n = 10
PET
sTNF-RI) with regional brain metabolism utilizing
(2013)
PET
T2: 1 year

PET.
post-tx
Key: Ctx+ = chemotherapy; Ctx- = no chemotherapy; fMRI = functional magnetic resonance imaging


576

Denise D. Correa and James C. Root

been found to be associated with serum inflammatory cytokines (TNFa; IL6) following treatment (Kesler, Janelsins,
et al., 2013). A potential role of DNA damage and its association with cortical gray matter was recently suggested in
a study by Conroy et al. (2013) that found higher oxidative
DNA damage in a sample of breast cancer survivors than in
healthy controls and associations of oxidative DNA damage
with gray matter density.
Treatment Interventions
Treatment of cognitive dysfunction in breast cancer patients
is a challenging clinical need and newly expanding area of
research. One particularly challenging aspect with regard to
rehabilitation in this cohort is the often significant but subtle
cognitive dysfunction exhibited in these patients. In contrast
to rehabilitation programs in traumatic brain injury or primary CNS tumors, the target of cognitive rehabilitation in
non-CNS cancers may be difficult to discern, and multiple
diffuse processes may be affected. Treatment has generally
taken the form of both compensatory and direct (restitutive)
rehabilitation, as well as cognitive behavioral therapy, and
pharmacologic treatment. Although it is not the focus of this
brief review, mindfulness-based programs and exercise regimens have also been considered either as alternatives to cognitive rehabilitation programs or as parts of a multitreatment
strategy. Generally, outcomes of treatment are promising but
the research on which they are based is still in the early stage

of development and no definitive conclusions can be drawn
from the handful of studies that have been conducted.
In an early, single-arm study to address treatment strategies for cognitive dysfunction following treatment (Ferguson,
Ahles, et al., 2007), a program of Memory and Attention
Adaptation Training (MAAT) was tested that included (a)
education on memory and attention; (b) self-awareness
training; (c) self-regulation via relaxation training; and (d)
compensatory strategy training. Improved self-reported and
objective cognitive function was found, along with adequate
feasibility and patient satisfaction, although no comparison
arm is available for assessing placebo and practice effects. In
a later, two-arm trial (Ferguson et al., 2012), patients were
randomized to receive either MAAT or assigned to a wait-list
control group. Patients treated with MAAT exhibited significantly improved verbal memory as compared to the wait list
control group, as well as significantly improved self-reported
“spiritual well-being,” although no significant effect was
found for other cognitive domains or for other self-reported
cognitive outcomes. Poppelreuter, Weis, and Bartsch (2009)
compared the effectiveness of computer-based training, and
a rehabilitation program to a control group at baseline, at
end of rehabilitation, and at six months, although no specific
effect of intervention was found, with all groups improving over time on measures of cognitive function. Von Ah
et al. (2012) studied effects of memory or processing speed
training versus a wait list control group at baseline, shortly

following training, and two months after completion of the
intervention, with significant effects for processing speed at
both the immediate and two month follow-up evaluation,
and significant memory effects at the two month follow-up
evaluation; interpretation of delayed effects are complicated

by no significant effect immediately following training. Cherrier et al. (2013) examined the effectiveness of a compensatory and mindfulness rehabilitation program versus control
at baseline and following training and found improvement
on self-reported cognitive function as well as in objective
attention functioning. In a cognitive-training rehabilitation
study, Kesler et al. (2013) utilized online training software
to examine remediation of executive functioning skills and
found significant improvements on the Wisconsin Card
Sorting Test, Symbol Search, and letter fluency in the active
treatment group versus controls, together with improved selfreported cognitive functioning in the active treatment group.
In addition to direct and compensatory rehabilitation programs, pharmacologic treatments have also been investigated
including modafanil and dexymethylphenidate. Results are
mixed regarding efficacy of dexymethylphenidate, with a
subset of studies finding significant improvement in fatigue
and cognition (Lower et al., 2009) while others find no beneficial effect (Mar Fan et al., 2008). Modafinil has received
increasing attention for its efficacy in treating cognitive dysfunction following treatment, again specifically with regard
to treatment of attentional dysfunction and fatigue, with
promising results (Kohli et al., 2009; Lundorff, Jonsson, &
Sjogren, 2009).

Conclusion
The recent literature suggests that both brain tumor and the
adverse effects of treatment contribute to cognitive dysfunction in a significant number of brain tumor patients. The
studies reviewed indicated that whole-brain RT alone or in
combination with chemotherapy result in more pronounced
cognitive dysfunction than either partial RT or chemotherapy alone. Antiepileptics and corticosteroids, often used
in the treatment of these patients, may also further disrupt
cognitive functioning. The cognitive domains suggested to
be particularly sensitive to treatment-induced cognitive dysfunction include several aspects of attention and executive
functions, learning and retrieval of new information, and
graphomotor speed.

Advancements in the field include the development of
guidelines for the use of standardized neuropsychological
tests in the context of clinical trials, and the inclusion of
cognitive outcome measures in several recent and ongoing
multi-center studies and clinical trials in neuro-oncology.
The findings from such studies would improve our understanding of the toxicity of various treatment modalities,
and enable both physicians and patients to make decisions
regarding treatment based not only on survival rates and
time to disease progression, but also on QoL.


Cognitive Functions in Adults With Cancers
In non-CNS cancers, the body of literature on selfreported cognitive dysfunction, cross-sectional and longitudinal objective cognitive assessments before and after
treatment, and structural and functional imaging findings
strongly support the occurrence of neuropsychological
dysfunction associated with diagnosis and treatment for
breast cancer. Cognitive changes may appear early in the
posttreatment course but may become more apparent after
physical/medical factors and concerns have resolved or
when patients attempt to return to prediagnosis responsibilities (school, work, household demands). Currently,
long-term effects are poorly understood, with the majority of studies suggesting persistent cognitive problems and
another subset suggesting relative resolution of difficulties
over time.
Recent studies have begun to describe the pathophysiological mechanisms that may underline the adverse effects
of RT and chemotherapy, and additional research is necessary to identify contributing factors for the development
of treatment-related cognitive dysfunction (e.g., genetic susceptibility). The efficacy of pharmacological and behavioral
interventions to improve cognitive function is increasingly
being investigated in studies involving patients with brain
tumors and non-CNS cancers.

References
Abraham, J., Haut, M. W., Moran, M. T., Filburn, S., Lemiuex, S.,
& Kuwabara, H. (2008). Adjuvant chemotherapy for breast cancer: Effects on cerebral white matter seen in diffusion tensor
imaging. Clinical Breast Cancer, 8(1), 88–91. doi: 10.3816/
CBC.2008.n.007
Abrey, L. E., Batchelor, T. T., Ferreri, A. J., Gospodarowicz, M.,
Pulczynski, E. J., Zucca, E., .  .  . International Primary,
C.N.S.L.C.G. (2005). Report of an international workshop to
standardize baseline evaluation and response criteria for primary
CNS lymphoma. Journal of Clinical Oncology, 23(22), 5034–
5043. doi: 10.1200/JCO.2005.13.524
Abrey, L. E., Olson, J. D., Raizer, J. J., Mack, M., Rodavitch, A.,
Boutros, D. Y., & Malkin, M. G. (2001). A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. Journal of Neuro-Oncology, 53(3), 259–265.
Ahles, T. A., Root, J. C., & Ryan, E. L. (2012). Cancer- and cancer
treatment-associated cognitive change: An update on the state of
the science. Journal of Clinical Oncology, 30(30), 3675–3686. doi:
10.1200/JCO.2012.43.0116
Ahles, T. A., & Saykin, A. J. (2007). Candidate mechanisms for
chemotherapy-induced cognitive changes. Nature Reviews Cancer, 7(3), 192–201. doi: 10.1038/nrc2073
Ahles, T. A., Saykin, A. J., Furstenberg, C. T., Cole, B., Mott, L. A.,
Skalla, K., . . . Silberfarb, P. M. (2002). Neuropsychologic impact of
standard-dose systemic chemotherapy in long-term survivors of breast
cancer and lymphoma. Journal of Clinical Oncology, 20(2), 485–493.
Ahles, T. A., Saykin, A. J., McDonald, B. C., Furstenberg, C. T.,
Cole, B. F., Hanscom, B. S., . . . Kaufman, P. A. (2008). Cognitive
function in breast cancer patients prior to adjuvant treatment.
Breast Cancer Research and Treatment, 110(1), 143–152.

577

Ahles, T. A., Saykin, A. J., McDonald, B. C., Li, Y., Furstenberg,
C. T., Hanscom, B. S., . . . Kaufman, P. A. (2010). Longitudinal
assessment of cognitive changes associated with adjuvant
treatment for breast cancer: Impact of age and cognitive
reserve. Journal of Clinical Oncology, 28(29), 4434–4440. doi:
10.1200/JCO.2009.27.0827
Ahles, T. A., Saykin, A. J., Noll, W. W., Furstenberg, C. T., Guerin,
S., Cole, B., & Mott, L. A. (2003). The relationship of APOE
genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology, 12(6), 612–619. doi: 10.1002/pon.742
Anderson, S. W., Damasio, H., & Tranel, D. (1990). Neuropsychological impairments associated with lesions caused by tumor or
stroke. Archives of Neurology, 47(4), 397–405.
Andrews, D. W., Scott, C. B., Sperduto, P. W., Flanders, A. E., Gaspar, L. E., Schell, M. C., . . . Curran, W. J., Jr. (2004). Whole
brain radiation therapy with or without stereotactic radiosurgery
boost for patients with one to three brain metastases: Phase III
results of the RTOG 9508 randomised trial. Lancet, 363(9422),
1665–1672. doi: 10.1016/S0140-6736(04)16250-8
Archibald, Y. M., Lunn, D., Ruttan, L. A., Macdonald, D. R., Del
Maestro, R. F., Barr, H. W., . . . Cairncross, J. G. (1994). Cognitive
functioning in long-term survivors of high-grade glioma. Journal
of Neurosurgery, 80(2), 247–253. doi: 10.3171/jns.1994.80.2.0247
Armstrong, C. L., Corn, B. W., Ruffer, J. E., Pruitt, A. A., Mollman,
J. E., & Phillips, P. C. (2000). Radiotherapeutic effects on brain
function: Double dissociation of memory systems. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 13(2), 101–111.
Armstrong, C. L., Goldstein, B., Shera, D., Ledakis, G. E., & Tallent, E. M. (2003). The predictive value of longitudinal neuropsychologic assessment in the early detection of brain tumor
recurrence. Cancer, 97(3), 649–656. doi: 10.1002/cncr.11099
Armstrong, C. L., Hunter, J. V., Ledakis, G. E., Cohen, B., Tallent,
E. M., Goldstein, B. H., . . . Phillips, P. (2002). Late cognitive and
radiographic changes related to radiotherapy: Initial prospective
findings. Neurology, 59(1), 40–48.
Armstrong, C. L., Stern, C. H., & Corn, B. W. (2001). Memory

performance used to detect radiation effects on cognitive functioning. Applied Neuropsychology, 8(3), 129–139. doi: 10.1207/
S15324826AN0803_1
Ayoma, H., Shirato, H., Tago, M., et al. (2006). Stereotactic radiosurgery plus whole-brain radiation therapy vs. stereotactic radiosurgery alone for treatment of brain metastases: A randomized
controlled trial. Journal of the American Medical Association,
295, 2483–2491.
Batchelor, T. T., Neuwelt, E., Wang, D. L., et al. (2012). Clinical and
diagnostic considerations in primary central nervous system lymphoma. In T. Batchelor & L. DeAngelis (Eds.), Lymphoma and Leukemia of the Nervous System (pp. 113–128). New York: Springer.
Behin, A., & Delattre, J.-Y. (2003). Neurologic sequelae of radiotherapy on the nervous system. In D. Schiff & P. Y. Wen (Eds.),
Cancer Neurology in Clinical Practice (pp. 173–191). Totowa, NJ:
Humana Press.
Bian, W., Hess, C. P., Chang, S. M., Nelson, S. J., & Lupo, J. M.
(2013). Computer-aided detection of radiation-induced cerebral
microbleeds on susceptibility-weighted MR images. NeuroImage:
Clinical, 2, 282–290. doi: 10.1016/j.nicl.2013.01.012
Biglia, N., Bounous, V. E., Malabaila, A., Palmisano, D., Torta, D. M.,
D’Alonzo, M., . . . Torta, R. (2012). Objective and self-reported cognitive dysfunction in breast cancer women treated with chemotherapy:


578

Denise D. Correa and James C. Root

A prospective study. European Journal of Cancer Care (English),
21(4), 485–492. doi: 10.1111/j.1365-2354.2011.01320.x
Boele, F. W., Douw, L., de Groot, M., van Thuijl, H. F., Cleijne, W.,
Heimans, J. J., . . . Klein, M. (2013). The effect of modafinil on
fatigue, cognitive functioning, and mood in primary brain tumor
patients: A multicenter randomized controlled trial. Neuro
Oncology, 15(10), 1420–1428. doi: 10.1093/neuonc/not102
Bondy, M. L., El-Zein, R., Wrench, M. (2005). Epidemiology of

brain cancer. In D. Schiff & B. P. O’Neill (Eds.), Principles of
Neuro-Oncology (pp. 3–16). New York: McGraw-Hill.
Boothe, D., Young, R., Yamada, Y., Prager, A., Chan, T., & Beal,
K. (2013). Bevacizumab as a treatment for radiation necrosis of
brain metastases post stereotactic radiosurgery. Neuro Oncology,
15(9), 1257–1263. doi: 10.1093/neuonc/not085
Bosma, I., Douw, L., Bartolomei, F., Heimans, J. J., van Dijk, B. W.,
Postma, T. J., . . . Klein, M. (2008). Synchronized brain activity
and neurocognitive function in patients with low-grade glioma:
A magnetoencephalography study. Neuro Oncology, 10(5), 734–
744. doi: 10.1215/15228517-2008-034
Bosma, I., Vos, M. J., Heimans, J. J., Taphoorn, M. J., Aaronson,
N. K., Postma, T. J., . . . Klein, M. (2007). The course of neurocognitive functioning in high-grade glioma patients. Neuro
Oncology, 9(1), 53–62. doi: 10.1215/15228517-2006-012
Brown, P. D., Asher, A. L., & Farace, E. (2008). Adjuvant whole
brain radiotherapy: Strong emotions decide but rational studies
are needed. International Journal of Radiation Oncology Biology
Physics, 70(5), 1305–1309. doi: 10.1016/j.ijrobp.2007.11.047
Brown, P. D., Jensen, A. W., Felten, S. J., Ballman, K. V., Schaefer,
P. L., Jaeckle, K. A., . . . Buckner, J. C. (2006). Detrimental effects
of tumor progression on cognitive function of patients with
high-grade glioma. Journal of Clinical Oncology, 24(34), 5427–
5433. doi: 10.1200/JCO.2006.08.5605
Brown, P. D., Pugh, S., Laack, N. N., Wefel, J. S., Khuntia, D.,
Meyers, C., . . . Radiation Therapy Oncology, G. (2013). Memantine for the prevention of cognitive dysfunction in patients
receiving whole-brain radiotherapy: A randomized, doubleblind, placebo-controlled trial. Neuro Oncology, 15(10), 1429–
1437. doi: 10.1093/neuonc/not114
BTPRG. (2000). Report of the Brain Tumor Progress Review Group.
Baltimore: National Institutes of Health.
Cairncross, J. G. (2000). Understanding low-grade glioma: A

decade of progress. Neurology, 54(7), 1402–1403.
Carson, K. A., Grossman, S. A., Fisher, J. D., & Shaw, E. G. (2007).
Prognostic factors for survival in adult patients with recurrent
glioma enrolled onto the new approaches to brain tumor therapy
CNS consortium phase I and II clinical trials. Journal of Clinical
Oncology, 25(18), 2601–2606. doi: 10.1200/JCO.2006.08.1661
Castellon, S. A., Ganz, P. A., Bower, J. E., Petersen, L., Abraham,
L., & Greendale, G. A. (2004). Neurocognitive performance in
breast cancer survivors exposed to adjuvant chemotherapy and
tamoxifen. Journal of Clinical and Experimental Neuropsychology, 26(7), 955–969.
Chang, E. L., Wefel, J. S., Hess, K. R., Allen, P. K., Lang, F. F.,
Kornguth, D. G., . . . Meyers, C. A. (2009). Neurocognition in
patients with brain metastases treated with radiosurgery or
radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncology, 10(11), 1037–1044. doi: 10.1016/
S1470-2045(09)70263-3
Chang, E. L., Wefel, J. S., Maor, M. H., Hassenbusch, S. J., 3rd,
Mahajan, A., Lang, F. F., . . . Meyers, C. A. (2007). A pilot study

of neurocognitive function in patients with one to three new
brain metastases initially treated with stereotactic radiosurgery
alone. Neurosurgery, 60(2), 277–283; discussion 283–274. doi:
10.1227/01.NEU.0000249272.64439.B1
Chapman, C. H., Nazem-Zadeh, M., Lee, O. E., Schipper, M. J.,
Tsien, C. I., Lawrence, T. S., & Cao, Y. (2013). Regional variation
in brain white matter diffusion index changes following chemoradiotherapy: A prospective study using tract-based spatial statistics. PLoS One, 8(3), e57768. doi: 10.1371/journal.pone.0057768
Cherrier, M. M., Anderson, K., David, D., Higano, C. S., Gray, H.,
Church, A., & Willis, S. L. (2013). A randomized trial of cognitive rehabilitation in cancer survivors. Life Sciences, 93(17), 617–
622. doi: 10.1016/j.lfs.2013.08.011
Cimprich, B., Reuter-Lorenz, P., Nelson, J., Clark, P. M., Therrien,
B., Normolle, D., . . . Welsh, R. C. (2010). Prechemotherapy alterations in brain function in women with breast cancer. Journal of

Clinical and Experimental Neuropsychology, 32(3), 324–331. doi:
10.1080/13803390903032537
Collins, B., Mackenzie, J., Stewart, A., Bielajew, C., & Verma, S.
(2009). Cognitive effects of chemotherapy in post-menopausal
breast cancer patients 1 year after treatment. Psychooncology,
18(2), 134–143. doi: 10.1002/pon.1379
Collins, B., MacKenzie, J., Tasca, G. A., Scherling, C., & Smith, A.
(2013a). Cognitive effects of chemotherapy in breast cancer
patients: A dose-response study. Psychooncology, 22(7), 1517–
1527. doi: 10.1002/pon.3163
Collins, B., MacKenzie, J., Tasca, G. A., Scherling, C., & Smith, A.
(2013b). Persistent cognitive changes in breast cancer patients 1
year following completion of chemotherapy. Journal of the International Neuropsychological Society , 1–10. doi: 10.1017/
S1355617713001215
Conroy, S. K., McDonald, B. C., Smith, D. J., Moser, L. R., West,
J. D., Kamendulis, L. M., . . . Saykin, A. J. (2013). Alterations in
brain structure and function in breast cancer survivors: Effect of
post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Research and Treatment, 137(2), 493–502. doi:
10.1007/s10549-012-2385-x
Constine, L. S., Konski, A., Ekholm, S., McDonald, S., & Rubin, P.
(1988). Adverse effects of brain irradiation correlated with MR and
CT imaging. International Journal of Radiation Oncology Biology
Physics, 15(2), 319–330.
Corn, B. W., Wang, M., Fox, S., Michalski, J., Purdy, J., Simpson,
J., . . . Movsas, B. (2009). Health related quality of life and cognitive status in patients with glioblastoma multiforme receiving
escalating doses of conformal three dimensional radiation on
RTOG 98–03. Journal of Neuro-Oncology, 95(2), 247–257. doi:
10.1007/s11060-009-9923-3
Correa, D. D. (2006). Cognitive functions in brain tumor patients.
Hematology/Oncology Clinics of North America, 20(6), 1363–

1376. doi: 10.1016/j.hoc.2006.09.012
Correa, D. D., & Ahles, T. A. (2008). Neurocognitive changes in
cancer survivors. Cancer Journal, 14(6), 396–400. doi: 10.1097/
PPO.0b013e31818d8769
Correa, D. D., Baser, R., Beal, K., et al. (2011). Longitudinal cognitive follow-up in newly diagnosed glioblastoma patients treated
with bevacizumab, temozolomide and hypofractionated stereotactic radiotherapy. Neuro Oncology, 15, 92.
Correa, D. D., DeAngelis, L. M., & Shi, W. (2007). Cognitive functions and APOE genotype in low grade glioma patients. Neuro
Oncology, 81, 175–184.


Cognitive Functions in Adults With Cancers
Correa, D. D., DeAngelis, L. M., Shi, W., Thaler, H., Glass, A., &
Abrey, L. E. (2004). Cognitive functions in survivors of primary
central nervous system lymphoma. Neurology, 62(4), 548–555.
Correa, D. D., & Hess, L. M. (2012). Cognitive function and quality of life in ovarian cancer. Gynecologic Oncology, 124(3), 404–
409. doi: 10.1016/j.ygyno.2011.11.005
Correa, D. D., Maron, L., Harder, H., Klein, M., Armstrong, C. L.,
Calabrese, P., . . . Schiff, D. (2007). Cognitive functions in primary central nervous system lymphoma: Literature review and
assessment guidelines. Annals of Oncology, 18(7), 1145–1151.
doi: 10.1093/annonc/mdl464
Correa, D. D., Rocco-Donovan, M., DeAngelis, L. M., DolgoffKaspar, R., Iwamoto, F., Yahalom, J., & Abrey, L. E. (2009).
Prospective cognitive follow-up in primary CNS lymphoma
patients treated with chemotherapy and reduced-dose radiotherapy. Journal of Neuro-Oncology, 91(3), 315–321. doi: 10.1007/
s11060-008-9716-0
Correa, D. D., Root, J. C., Baser, R., Moore, D., Peck, K. K., Lis,
E., . . . Relkin, N. (2013). A prospective evaluation of changes in
brain structure and cognitive functions in adult stem cell transplant recipients. Brain Imaging and Behavior, 7(4), 478–490. doi:
10.1007/s11682-013-9221-8
Correa, D. D., Satagopan, J., Baser, R. E., Cheung, K., Lin, M.,
Karimi, S., . . . Orlow, I. (2013). APOE genotype and cognitive

outcome in patients with brain tumors. Neuro Oncology, 15, 93.
Correa, D. D., Shi, W., Abrey, L. E., Deangelis, L. M., Omuro, A. M.,
Deutsch, M. B., & Thaler, H. T. (2012). Cognitive functions in primary CNS lymphoma after single or combined modality regimens.
Neuro Oncology, 14(1), 101–108. doi: 10.1093/neuonc/nor186
Correa, D. D., Shi, W., Thaler, H. T., Cheung, A. M., DeAngelis, L.
M., & Abrey, L. E. (2008). Longitudinal cognitive follow-up in
low grade gliomas. Journal of Neuro-Oncology, 86(3), 321–327.
doi: 10.1007/s11060-007-9474-4
Correa, D. D., Zhou, Q., Thaler, H. T., Maziarz, M., Hurley, K., &
Hensley, M. L. (2010). Cognitive functions in long-term survivors of ovarian cancer. Gynecologic Oncology, 119(2), 366–369.
doi: 10.1016/j.ygyno.2010.06.023
Crossen, J. R., Garwood, D., Glatstein, E., & Neuwelt, E. A.
(1994). Neurobehavioral sequelae of cranial irradiation in adults:
A review of radiation-induced encephalopathy. Journal of Clinical Oncology, 12(3), 627–642.
Crossen, J. R., Goldman, D. L., Dahlborg, S. A., & Neuwelt, E. A.
(1992). Neuropsychological assessment outcomes of nonacquired immunodeficiency syndrome patients with primary central nervous system lymphoma before and after blood-brain
barrier disruption chemotherapy. Neurosurgery, 30(1), 23–29.
Cull, A., Hay, C., Love, S. B., Mackie, M., Smets, E., & Stewart, M.
(1996). What do cancer patients mean when they complain of
concentration and memory problems? British Journal of Cancer,
74(10), 1674–1679.
Cull, A., Stewart, M., & Altman, D. G. (1995). Assessment of and
intervention for psychosocial problems in routine oncology practice. British Journal of Cancer, 72(1), 229–235.
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surfacebased analysis: I. Segmentation and surface reconstruction. Neuroimage, 9(2), 179–194.
DeAngelis, L. M., & Posner, J. B. (2009). Side effects of radiation
therapy. In L. M. DeAngelis & J. B. Posner (Eds.), Neurologic
Complications of Cancer (2nd ed., pp.  551–555). New York:
Oxford University Press.

579

DeAngelis, L. M., Seiferheld, W., Schold, S. C., Fisher, B., Schultz,
C. J., & Radiation Therapy Oncology Group, S. (2002). Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group
Study 93–10. Journal of Clinical Oncology, 20(24), 4643–4648.
DeAngelis, L. M., & Shapiro, W. R. (1991). Drug/radiation interactions and central nervous system injury. In P. H. Gutin, S. A.
Leibel, & G. E. Sheline (Eds.), Radiation Injury to the Nervous
System (pp. 361–382). New York: Raven Press.
DeAngelis, L. M., Yahalom, J., Thaler, H. T., & Kher, U. (1992).
Combined modality therapy for primary CNS lymphoma. Journal of Clinical Oncology, 10(4), 635–643.
Debess, J., Riis, J. O., Pedersen, L., & Ewertz, M. (2009). Cognitive
function and quality of life after surgery for early breast cancer
in North Jutland, Denmark. Acta Oncologica, 48(4), 532–540.
doi: 906989492 [pii] 10.1080/02841860802600755
DeGroot, J. F., Aldape, K. D., & Colman, H. (2005). High-grade
astrocytomas. In D. Schiff & B. P. O’Neill (Eds.), Principles of
Neuro-Oncology (pp. 259–288). New York: McGraw-Hill.
de Groot, M., Douw, L., Sizoo, E. M., Bosma, I., Froklage, F. E.,
Heimans, J. J., .  .  . Reijneveld, J. C. (2013). Levetiracetam
improves verbal memory in high-grade glioma patients. Neuro
Oncology, 15(2), 216–223. doi: 10.1093/neuonc/nos288
Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., Van
Hecke, W., . . . Sunaert, S. (2012). Longitudinal assessment of
chemotherapy-induced structural changes in cerebral white matter
and its correlation with impaired cognitive functioning. Journal of
Clinical Oncology, 30(3), 274–281. doi: 10.1200/JCO.2011.36.8571
Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den
Stock, J., . . . Sunaert, S. (2011). Chemotherapy-induced structural changes in cerebral white matter and its correlation with
impaired cognitive functioning in breast cancer patients. Human
Brain Mapping, 32(3), 480–493. doi: 10.1002/hbm.21033
Deprez, S., Billiet, T., Sunaert, S., & Leemans, A. (2013). Diffusion

tensor MRI of chemotherapy-induced cognitive impairment in
non-CNS cancer patients: A review. Brain Imaging and Behavior,
7(4), 409–435. doi: 10.1007/s11682-012-9220-1
de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., Caan,
M., Douaud, G., . . . Schagen, S. B. (2011). Late effects of high-dose
adjuvant chemotherapy on white and gray matter in breast cancer
survivors: Converging results from multimodal magnetic resonance
imaging. Human Brain Mapping. doi: 10.1002/hbm.21422
de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., van
Dam, F. S., Nederveen, A. J., . . . Schagen, S. B. (2011). Cerebral
hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Human Brain Mapping, 32(8),
1206–1219. doi: 10.1002/hbm.21102
de Ruiter, M. B., & Schagen, S. B. (2013). Functional MRI studies
in non-CNS cancers. Brain Imaging and Behavior, 7(4), 388–408.
doi: 10.1007/s11682-013-9249-9
De Witt Hamer, P. C., Robles, S. G., Zwinderman, A. H., Duffau, H.,
& Berger, M. S. (2012). Impact of intraoperative stimulation brain
mapping on glioma surgery outcome: A meta-analysis. Journal of
Clinical Oncology, 30(20), 2559–2565. doi: 10.1200/JCO.2011.38.4818
Dietrich, J. (2010). Chemotherapy associated central nervous system
damage. In R. B. Raffa & R. J. Tallarida (Eds.), Chemo Fog: Cancer
Chemotherapy-Related Cognitive Impairment (pp. 77–85). Austin,
TX: Landes Bioscience and Springer Science and Business Media.
Dietrich, J., Han, R., Yang, Y., Mayer-Proschel, M., & Noble, M.
(2006). CNS progenitor cells and oligodendrocytes are targets of


580

Denise D. Correa and James C. Root

chemotherapeutic agents in vitro and in vivo. Journal of Biology,
5(7), 1–23. doi: 10.1186/jbiol50
Dietrich, J., Monje, M., Wefel, J., & Meyers, C. (2008). Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist, 13(12), 1285–1295. doi:
10.1634/theoncologist.2008-0130
Donovan, K. A., Small, B. J., Andrykowski, M. A., Schmitt, F. A.,
Munster, P., & Jacobsen, P. B. (2005). Cognitive functioning after
adjuvant chemotherapy and/or radiotherapy for early-stage
breast carcinoma. Cancer, 104(11), 2499–2507. doi: 10.1002/
cncr.21482
Doolittle, N. D., Dosa, E., Fu, R., Muldoon, L. L., Maron, L. M.,
Lubow, M. A., . . . Neuwelt, E. A. (2013). Preservation of cognitive function in primary CNS lymphoma survivors a median of
12 years after enhanced chemotherapy delivery. Journal of Clinical Oncology, 31(31), 4026–4027. doi: 10.1200/JCO.2013.52.7747
Doolittle, N. D., Korfel, A., Lubow, M. A., Schorb, E., Schlegel,
U., Rogowski, S., . . . Neuwelt, E. A. (2013). Long-term cognitive
function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology , 81 (1), 84–92. doi: 10.1212/
WNL.0b013e318297eeba
Douw, L., Klein, M., Fagel, S. S., van den Heuvel, J., Taphoorn, M.
J., Aaronson, N. K., . . . Heimans, J. J. (2009). Cognitive and
radiological effects of radiotherapy in patients with low-grade
glioma: Long-term follow-up. Lancet Neurology, 8(9), 810–818.
doi: 10.1016/S1474-4422(09)70204-2
Downie, F. P., Mar Fan, H. G., Houede-Tchen, N., Yi, Q., & Tannock, I. F. (2006). Cognitive function, fatigue, and menopausal
symptoms in breast cancer patients receiving adjuvant chemotherapy: Evaluation with patient interview after formal assessment. Psychooncology, 15(10), 921–930. doi: 10.1002/pon.1035
Duffau, H. (2005). Lessons from brain mapping in surgery for lowgrade glioma: Insights into associations between tumour and
brain plasticity. Lancet Neurology, 4(8), 476–486. doi: 10.1016/
S1474-4422(05)70140-X
Duffey, P., Chari, G., Cartlidge, N. E., & Shaw, P. J. (1996). Progressive deterioration of intellect and motor function occurring several decades after cranial irradiation: A new facet in the clinical
spectrum of radiation encephalopathy. Archives of Neurology,
53(8), 814–818.

Dumas, J. A., Makarewicz, J., Schaubhut, G. J., Devins, R., Albert,
K., Dittus, K., & Newhouse, P. A. (2013). Chemotherapy altered
brain functional connectivity in women with breast cancer: A
pilot study. Brain Imaging and Behavior, 7(4), 524–532. doi:
10.1007/s11682-013-9244-1
Fan, H. G., Houede-Tchen, N., Yi, Q. L., Chemerynsky, I., Downie,
F. P., Sabate, K., & Tannock, I. F. (2005). Fatigue, menopausal
symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of a prospective controlled study. Journal of Clinical Oncology, 23(31),
8025–8032. doi: 10.1200/JCO.2005.01.6550
Ferguson, R. J., Ahles, T. A., Saykin, A. J., McDonald, B. C., Furstenberg, C. T., Cole, B. F., & Mott, L. A. (2007). Cognitivebehavioral management of chemotherapy-related cognitive
change. Psychooncology, 16(8), 772–777. doi: 10.1002/pon.1133
Ferguson, R. J., McDonald, B. C., Rocque, M. A., Furstenberg, C.
T., Horrigan, S., Ahles, T. A., & Saykin, A. J. (2012). Development of CBT for chemotherapy-related cognitive change: Results
of a waitlist control trial. Psychooncology, 21(2), 176–186. doi:
10.1002/pon.1878

Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A.
(2007). Brain structure and function differences in monozygotic
twins: Possible effects of breast cancer chemotherapy. Journal of
Clinical Oncology, 25(25), 3866–3870.
Ferreri, A. J., Zucca, E., Armitage, J., Cavalli, F., & Batchelor, T. T. (2013).
Ten years of international primary CNS lymphoma collaborative
group studies. Journal of Clinical Oncology, 31(27), 3444–3445.
Fike, J. R., Rosi, S., & Limoli, C. L. (2009). Neural precursor
cells and central nervous system radiation sensitivity. Seminars
in Radiation Oncology , 19(2), 122–132. doi: 10.1016/j.
semradonc.2008.12.003
Fishel, M. L., Vasko, M. R., & Kelley, M. R. (2007). DNA repair
in neurons: So if they don’t divide what’s to repair? Mutation
Research, 614(1–2), 24–36. doi: 10.1016/j.mrfmmm.2006.06.007

Fliessbach, K., Helmstaedter, C., Urbach, H., Althaus, A., Pels, H.,
Linnebank, M., . . . Schlegel, U. (2005). Neuropsychological outcome after chemotherapy for primary CNS lymphoma: A prospective study. Neurology, 64(7), 1184–1188. doi: 10.1212/01.
WNL.0000156350.49336.E2
Froklage, F. E., Oosterbaan, L. J., Sizoo, E. M., de Groot, M.,
Bosma, I., Sanchez, E., . . . Postma, T. J. (2013). Central neurotoxicity of standard treatment in patients with newly diagnosed
high-grade glioma: A prospective longitudinal study. Journal of
Neuro-Oncology, 116(2), 387–394.
Gehring, K., Aaronson, N. K., Taphoorn, M. J., & Sitskoorn, M.
M. (2010). Interventions for cognitive deficits in patients with a
brain tumor: An update. Expert Review of Anticancer Therapy,
10(11), 1779–1795. doi: 10.1586/era.10.163
Gehring, K., Patwardhan, S. Y., Collins, R., Groves, M. D., Etzel,
C. J., Meyers, C. A., & Wefel, J. S. (2012). A randomized trial on
the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary
brain tumor. Journal of Neuro-Oncology, 107(1), 165–174. doi:
10.1007/s11060-011-0723-1
Gehring, K., Sitskoorn, M. M., Aaronson, N. K., & Taphoorn, M.
J. (2008). Interventions for cognitive deficits in adults with brain
tumours. Lancet Neurology, 7(6), 548–560. doi: 10.1016/
S1474-4422(08)70111-X
Ghia, A., Tome, W. A., Thomas, S., Cannon, G., Khuntia, D., Kuo,
J. S., & Mehta, M. P. (2007). Distribution of brain metastases in
relation to the hippocampus: Implications for neurocognitive
functional preservation. International Journal of Radiation
Oncology Biology Physics, 68(4), 971–977. doi: 10.1016/j.
ijrobp.2007.02.016
Gilbert, M. R., Dignam, J. J., Armstrong, T. S., Wefel, J. S., Blumenthal, D. T., Vogelbaum, M. A., . . . Mehta, M. P. (2014). A
randomized trial of bevacizumab for newly diagnosed glioblastoma. The New England Journal of Medicine, 370(8), 699–708.
Gondi, V., Hermann, B. P., Mehta, M. P., & Tome, W. A. (2013).
Hippocampal dosimetry predicts neurocognitive function

impairment after fractionated stereotactic radiotherapy for
benign or low-grade adult brain tumors. International Journal of
Radiation Oncology Biology Physics, 85(2), 348–354. doi:
10.1016/j.ijrobp.2012.11.031
Gondi, V., Mehta, M., Pugh, S., et al. (2013). Memory preservation
with conformal avoidance of the hippocampus during wholebrain radiotherapy (WBRT) for patients with brain metastases:
Preliminary results of RTOG 0933. Neuro Oncology, 15, 94.
Greenberg, H. S., Chandler, W. F., & Sandler, H. M. (1999). Brain
tumor classification, grading and epidemiology. In W. Chandler,


Cognitive Functions in Adults With Cancers
H. S. Greenberg, & H. M. Sandler (Eds.), Brain Tumors (p. 1026).
New York: Oxford University Press.
Greene-Schloesser, D., Moore, E., & Robbins, M. E. (2013). Molecular pathways: Radiation-induced cognitive impairment. Clinical
Cancer Research, 19 (9), 2294–2300. doi: 10.1158/1078-0432.
CCR-11-2903
Greene-Schloesser, D., Robbins, M. E., Peiffer, A. M., Shaw, E. G.,
Wheeler, K. T., & Chan, M. D. (2012). Radiation-induced brain
injury: A review. Frontiers in Oncology, 2, 1–18. doi: 10.3389/
fonc.2012.00073
Habets, E. J., Taphoorn, M. J., Nederend, S., Klein, M., Delgadillo,
D., Hoang-Xuan, K., . . . Reijneveld, J. C. (2014). Health-related
quality of life and cognitive functioning in long-term anaplastic
oligodendroglioma and oligoastrocytoma survivors. Journal of
Neuro-Oncology, 116(1), 161–168. doi: 10.1007/s11060-013-1278-0
Hahn, C. A., Zhou, S. M., Raynor, R., Tisch, A., Light, K., Shafman, T., .  .  . Marks, L. B. (2009). Dose-dependent effects of
radiation therapy on cerebral blood flow, metabolism, and neurocognitive dysfunction. International Journal of Radiation
Oncology Biology Physics, 73(4), 1082–1087. doi: 10.1016/j.
ijrobp.2008.05.061

Harder, H., Holtel, H., Bromberg, J. E., Poortmans, P., HaaxmaReiche, H., Kluin-Nelemans, H. C., .  .  . van den Bent, M. J.
(2004). Cognitive status and quality of life after treatment for
primary CNS lymphoma. Neurology, 62(4), 544–547.
Hedayati, E., Alinaghizadeh, H., Schedin, A., Nyman, H., & Albertsson, M. (2012). Effects of adjuvant treatment on cognitive function in women with early breast cancer. European Journal of
Oncology Nursing, 16(3), 315–322. doi: 10.1016/j.ejon.2011.07.006
Herman, M. A., Tremont-Lukats, I., Meyers, C. A., Trask, D. D.,
Froseth, C., Renschler, M. F., & Mehta, M. P. (2003). Neurocognitive and functional assessment of patients with brain metastases: A pilot study. American Journal of Clinical Oncology, 26(3),
273–279. doi: 10.1097/01.COC.0000020585.85901.7C
Hermelink, K., Untch, M., Lux, M. P., Kreienberg, R., Beck, T.,
Bauerfeind, I., & Munzel, K. (2007). Cognitive function during
neoadjuvant chemotherapy for breast cancer: Results of a prospective, multicenter, longitudinal study. Cancer, 109(9), 1905–
1913. doi: 10.1002/cncr.22610
Hilverda, K., Bosma, I., Heimans, J. J., Postma, T. J., Peter Vandertop, W., Slotman, B. J., . . . Klein, M. (2010). Cognitive functioning in glioblastoma patients during radiotherapy and
temozolomide treatment: Initial findings. Journal of NeuroOncology, 97(1), 89–94. doi: 10.1007/s11060-009-9993-2
Hom, J., & Reitan, R. M. (1984). Neuropsychological correlates of
rapidly vs. slowly growing intrinsic cerebral neoplasms. Journal
of Clinical Neuropsychology, 6(3), 309–324.
Hurria, A., Somlo, G., & Ahles, T. (2007). Renaming “chemobrain.” Cancer Investigation, 25(6), 373–377. doi: 782023378 [pii]
10.1080/07357900701506672
Imperato, J. P., Paleologos, N. A., & Vick, N. A. (1990). Effects of
treatment on long-term survivors with malignant astrocytomas.
Annals of Neurology, 28(6), 818–822. doi: 10.1002/ana.410280614
Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T.,
Akechi, T., . . . Uchitomi, Y. (2007). Smaller regional volumes of
brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer, 109(1), 146–156.
Jamadar, R. J., Winters, M. J., & Maki, P. M. (2012). Cognitive
changes associated with ADT: A review of the literature. Asian
Journal of Andrology, 14(2), 232–238. doi: 10.1038/aja.2011.107

581

Jansen, C. E., Cooper, B. A., Dodd, M. J., & Miaskowski, C. A.
(2011). A prospective longitudinal study of chemotherapyinduced cognitive changes in breast cancer patients. Support Care
Cancer, 19(10), 1647–1656. doi: 10.1007/s00520-010-0997-4
Jansen, C. E., Dodd, M. J., Miaskowski, C. A., Dowling, G. A., &
Kramer, J. (2008). Preliminary results of a longitudinal study of
changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology, 17(12), 1189–1195. doi: 10.1002/pon.1342
Jenkins, V., Shilling, V., Deutsch, G., Bloomfield, D., Morris, R.,
Allan, S., . . . Winstanley, J. (2006). A 3-year prospective study of
the effects of adjuvant treatments on cognition in women with
early stage breast cancer. British Journal of Cancer, 94(6), 828–
834. doi: 10.1038/sj.bjc.6603029
Jim, H. S., Donovan, K. A., Small, B. J., Andrykowski, M. A.,
Munster, P. N., & Jacobsen, P. B. (2009). Cognitive functioning
in breast cancer survivors: A controlled comparison. Cancer,
115(8), 1776–1783. doi: 10.1002/cncr.24192
Johnson, D. R., Sawyer, A. M., Meyers, C. A., O’Neill, B. P., &
Wefel, J. S. (2012). Early measures of cognitive function predict
survival in patients with newly diagnosed glioblastoma. Neuro
Oncology, 14(6), 808–816. doi: 10.1093/neuonc/nos082
Johnson, D. R., & Wefel, J. S. (2013). Relationship between cognitive function and prognosis in glioblastoma. CNS Oncology, 2,
195–201.
Juergens, A., Pels, H., Rogowski, S., Fliessbach, K., Glasmacher,
A., Engert, A., . . . Schlegel, U. (2010). Long-term survival with
favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Annals of Neurology, 67(2), 182–
189. doi: 10.1002/ana.21824
Kayl, A. E., & Meyers, C. A. (2003). Does brain tumor histology
influence cognitive function? Neuro Oncology, 5(4), 255–260. doi:
10.1215/S1152851703000012
Keime-Guibert, F., Napolitano, M., & Delattre, J. Y. (1998). Neurological complications of radiotherapy and chemotherapy.

Journal of Neurology, 245(11), 695–708.
Kesler, S. R., Bennett, F. C., Mahaffey, M. L., & Spiegel, D. (2009).
Regional brain activation during verbal declarative memory in
metastatic breast cancer. Clinical Cancer Research, 15(21), 6665–
6673. doi: 10.1158/1078-0432.CCR-09-1227
Kesler, S. R., Hadi Hosseini, S. M., Heckler, C., Janelsins, M.,
Palesh, O., Mustian, K., & Morrow, G. (2013). Cognitive training for improving executive function in chemotherapy-treated
breast cancer survivors. Clinical Breast Cancer, 13(4), 299–306.
doi: 10.1016/j.clbc.2013.02.004
Kesler, S. R., Janelsins, M., Koovakkattu, D., Palesh, O., Mustian,
K., Morrow, G., & Dhabhar, F. S. (2013). Reduced hippocampal
volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behavior and Immunity,
(Suppl 30), S109–S116. doi: 10.1016/j.bbi.2012.05.017
Kesler, S. R., Kent, J. S., & O’Hara, R. (2011). Prefrontal cortex
and executive function impairments in primary breast cancer.
Archives of Neurology , 68 (11), 1447–1453. doi: 10.1001/
archneurol.2011.245
Khasraw, M., Ashley, D., Wheeler, G., & Berk, M. (2012). Using
lithium as a neuroprotective agent in patients with cancer. BMC
Medicine, 10, 131. doi: 10.1186/1741-7015-10-131
Kiebert, G. M., Curran, D., Aaronson, N. K., Bolla, M., Menten,
J., Rutten, E. H., . . . Karim, A. B. (1998). Quality of life after


582

Denise D. Correa and James C. Root

radiation therapy of cerebral low-grade gliomas of the adult:
Results of a randomised phase III trial on dose response (EORTC

trial 22844). EORTC Radiotherapy Co-operative Group. European Journal of Cancer, 34(12), 1902–1909.
Kim, J. H., Brown, S. L., Jenrow, K. A., & Ryu, S. (2008). Mechanisms of radiation-induced brain toxicity and implications for
future clinical trials. Journal of Neuro-Oncology, 87(3), 279–286.
doi: 10.1007/s11060-008-9520-x
Klein, M. (2012). Neurocognitive functioning in adult WHO grade
II gliomas: Impact of old and new treatment modalities.
Neuro Oncology, 14(Suppl 4), iv17–24. doi: 10.1093/neuonc/
nos161
Klein, M., Heimans, J. J., Aaronson, N. K., van der Ploeg, H. M.,
Grit, J., Muller, M., . . . Taphoorn, M. J. (2002). Effect of radiotherapy and other treatment-related factors on mid-term to longterm cognitive sequelae in low-grade gliomas: A comparative
study. Lancet, 360(9343), 1361–1368.
Klein, M., Postma, T. J., Taphoorn, M. J., Aaronson, N. K.,
Vandertop, W. P., Muller, M., . . . Heimans, J. J. (2003). The prognostic value of cognitive functioning in the survival of patients
with high-grade glioma. Neurology, 61(12), 1796–1798.
Klein, M., Taphoorn, M. J., Heimans, J. J., van der Ploeg, H. M.,
Vandertop, W. P., Smit, E. F., . . . Aaronson, N. K. (2001). Neurobehavioral status and health-related quality of life in newly
diagnosed high-grade glioma patients. Journal of Clinical Oncology, 19(20), 4037–4047.
Kleinberg, L., Wallner, K., & Malkin, M. G. (1993). Good performance status of long-term disease-free survivors of intracranial
gliomas. International Journal of Radiation Oncology Biology
Physics, 26(1), 129–133.
Kocher, M., Soffietti, R., Abacioglu, U., Villa, S., Fauchon, F., Baumert, B. G., .  .  . Mueller, R. P. (2011). Adjuvant whole-brain
radiotherapy versus observation after radiosurgery or surgical
resection of one to three cerebral metastases: Results of the
EORTC 22952–26001 study. Journal of Clinical Oncology, 29(2),
134–141. doi: 10.1200/JCO.2010.30.1655
Kohli, S., Fisher, S. G., Tra, Y., Adams, M. J., Mapstone, M. E.,
Wesnes, K. A., . . . Morrow, G. R. (2009). The effect of modafinil
on cognitive function in breast cancer survivors. Cancer, 115(12),
2605–2616. doi: 10.1002/cncr.24287
Koppelmans, V., Breteler, M. M., Boogerd, W., Seynaeve, C.,

Gundy, C., & Schagen, S. B. (2012). Neuropsychological performance in survivors of breast cancer more than 20 years after
adjuvant chemotherapy. Journal of Clinical Oncology, 30(10),
1080–1086. doi: 10.1200/JCO.2011.37.0189
Koppelmans, V., de Groot, M., de Ruiter, M. B., Boogerd, W., Seynaeve, C., Vernooij, M. W., . . . Breteler, M. M. (2014). Global
and focal white matter integrity in breast cancer survivors 20
years after adjuvant chemotherapy. Human Brain Mapping,
35(3), 889–899. doi: 10.1002/hbm.22221
Koppelmans, V., de Ruiter, M. B., van der Lijn, F., Boogerd, W.,
Seynaeve, C., van der Lugt, A., . . . Schagen, S. B. (2011). Global
and focal brain volume in long-term breast cancer survivors
exposed to adjuvant chemotherapy. Breast Cancer Research and
Treatment. doi: 10.1007/s10549-011-1888-1
Laack, N. N., Brown, P. D., Furth, A., et al. (2003). Neurocognitive
function after radiotherapy (RT) for supratentorial low-grade
gliomas (LGG): Results of a north central cancer treatment
group (NCCTG) prospective study. International Journal of
Radiation Oncology Biology Physics, 57, S134.

Lassman, A. B., & DeAngelis, L. M. (2003). Brain metastases. Neurologic Clinics, 21(1), 1–23, vii.
Lee, W. H., Sonntag, W. E., Mitschelen, M., Yan, H., & Lee, Y. W.
(2010). Irradiation induces regionally specific alterations in proinflammatory environments in rat brain. International Journal of
Radiation Biology, 86(2), 132–144. doi: 10.3109/09553000903419346
Levin, V. A., Bidaut, L., Hou, P., Kumar, A. J., Wefel, J. S., Bekele,
B. N., . . . Jackson, E. F. (2011). Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation
necrosis of the central nervous system. International Journal of
Radiation Oncology Biology Physics, 79(5), 1487–1495. doi:
10.1016/j.ijrobp.2009.12.061
Li, J., Bentzen, S. M., Renschler, M., & Mehta, M. P. (2007).
Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. Journal of Clinical Oncology, 25(10), 1260–1266. doi:
10.1200/JCO.2006.09.2536

Lin, N. U., Wefel, J. S., Lee, E. Q., et al. (2013). Challenges relating
to solid tumour brain metastases in clinical trials, part 2: Neurocognitive, neurological, and quality-o-life outcomes: A report
from the RANO group. Lancet Oncology, 14, e407–416.
Locke, D. E., Cerhan, J. H., Wu, W., Malec, J. F., Clark, M. M.,
Rummans, T. A., & Brown, P. D. (2008). Cognitive rehabilitation
and problem-solving to improve quality of life of patients with
primary brain tumors: A pilot study. The Journal of Supportive
Oncology, 6(8), 383–391.
Lopez Zunini, R. A., Scherling, C., Wallis, N., Collins, B., MacKenzie, J., Bielajew, C., & Smith, A. M. (2013). Differences in verbal
memory retrieval in breast cancer chemotherapy patients compared to healthy controls: A prospective fMRI study. Brain Imaging and Behavior, 7(4), 460–477. doi: 10.1007/s11682-012-9213-0
Lower, E. E., Fleishman, S., Cooper, A., Zeldis, J., Faleck, H., Yu, Z.,
& Manning, D. (2009). Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical
trial. Journal of Pain and Symptom Management, 38, 650–662.
Lubelski, D., Abdullah, K. G., Weil, R. J., & Marko, N. F. (2013).
Bevacizumab for radiation necrosis following treatment of high
grade glioma: A systematic review of the literature. Journal of
Neuro-Oncology, 115(3), 317–322. doi: 10.1007/s11060-013-1233-0
Lundorff, L. E., Jonsson, B. H., & Sjogren, P. (2009). Modafinil for
attentional and psychomotor dysfunction in advanced cancer: A
double-blind, randomised, cross-over trial. Palliative Medicine,
23(8), 731–738. doi: 10.1177/0269216309106872
Lupien, S. J., Gillin, C. J., & Hauger, R. L. (1999). Working memory is more sensitive than declarative memory to the acute effects
of corticosteroids: A dose-response study in humans. Behavioral
Neuroscience, 113(3), 420–430.
Madsen, T. M., Kristjansen, P. E., Bolwig, T. G., & Wortwein, G.
(2003). Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult
rat. Neuroscience, 119(3), 635–642.
Mar Fan, H. G., Clemons, M., Xu, W., Chemerynsky, I., Breunis,
H., Braganza, S., & Tannock, I. F. (2008). A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing
adjuvant chemotherapy for breast cancer. Support Care Cancer,

16(6), 577–583. doi: 10.1007/s00520-007-0341-9
Mauer, M., Stupp, R., Taphoorn, M. J., Coens, C., Osoba, D.,
Marosi, C., . . . Bottomley, A. (2007). The prognostic value of
health-related quality-of-life data in predicting survival in


Cognitive Functions in Adults With Cancers
glioblastoma cancer patients: Results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study. British
Journal of Cancer, 97(3), 302–307. doi: 10.1038/sj.bjc.6603876
McAllister, L. D., Doolittle, N. D., Guastadisegni, P. E., Kraemer,
D. F., Lacy, C. A., Crossen, J. R., & Neuwelt, E. A. (2000). Cognitive outcomes and long-term follow-up results after enhanced
chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery, 46(1), 51–60; discussion 60–51.
McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin,
A. J. (2010). Gray matter reduction associated with systemic chemotherapy for breast cancer: A prospective MRI study. Breast
Cancer Research and Treatment.
McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin,
A. J. (2012). Alterations in brain activation during working memory processing associated with breast cancer and treatment: A
prospective functional magnetic resonance imaging study. Journal of Clinical Oncology, 30(20), 2500–2508. doi: 10.1200/
JCO.2011.38.5674
McDonald, B. C., Conroy, S. K., Smith, D. J., West, J. D., & Saykin,
A. J. (2013). Frontal gray matter reduction after breast cancer
chemotherapy and association with executive symptoms: A replication and extension study. Brain Behavior and Immunity,
(Suppl 30), S117–125. doi: 10.1016/j.bbi.2012.05.007
McDonald, B. C., & Saykin, A. J. (2013). Alterations in brain structure related to breast cancer and its treatment: Chemotherapy
and other considerations. Brain Imaging and Behavior, 7(4), 374–
387. doi: 10.1007/s11682-013-9256-x
McDuff, S. G., Taich, Z. J., Lawson, J. D., Sanghvi, P., Wong, E. T.,
Barker, F. G., 2nd, . . . Chen, C. C. (2013). Neurocognitive assessment following whole brain radiation therapy and radiosurgery
for patients with cerebral metastases. Journal of Neurology, Neurosurgery, and Psychiatry, 84(12), 1384–1391. doi: 10.1136/
jnnp-2013-305166

Mehlsen, M., Pedersen, A. D., Jensen, A. B., & Zachariae, R.
(2009). No indications of cognitive side-effects in a prospective
study of breast cancer patients receiving adjuvant chemotherapy.
Psychooncology, 18(3), 248–257. doi: 10.1002/pon.1398
Mehnert, A., Scherwath, A., Schirmer, L., Schleimer, B., Petersen,
C., Schulz-Kindermann, F., . . . Koch, U. (2007). The association
between neuropsychological impairment, self-perceived cognitive deficits, fatigue and health related quality of life in breast
cancer survivors following standard adjuvant versus high-dose
chemotherapy. Patient Education and Counseling, 66(1), 108–118.
doi: 10.1016/j.pec.2006.11.005
Mehta, M. P., Shapiro, W. R., Phan, S. C., Gervais, R., Carrie, C.,
Chabot, P., . . . Renschler, M. F. (2009). Motexafin gadolinium
combined with prompt whole brain radiotherapy prolongs time
to neurologic progression in non-small-cell lung cancer patients
with brain metastases: Results of a phase III trial. International
Journal of Radiation Oncology Biology Physics, 73(4), 1069–
1076. doi: 10.1016/j.ijrobp.2008.05.068
Mehta, M. P., & Tremont-Lukas, I. (2004). Radiosurgery for Single
and Multiple Metastases. Malden, MA: Blackwell.
Meyers, C. A., & Brown, P. D. (2006). Role and relevance of neurocognitive assessment in clinical trials of patients with CNS
tumors. Journal of Clinical Oncology, 24(8), 1305–1309. doi:
10.1200/JCO.2005.04.6086
Meyers, C. A., & Hess, K. R. (2003). Multifaceted end points in
brain tumor clinical trials: Cognitive deterioration precedes MRI

583

progression. Neuro Oncology, 5(2), 89–95. doi: 10.1215/S1522-851702-00026-1
Meyers, C. A., Hess, K. R., Yung, W. K., & Levin, V. A. (2000). Cognitive function as a predictor of survival in patients with recurrent
malignant glioma. Journal of Clinical Oncology, 18(3), 646–650.

Meyers, C. A., Smith, J. A., Bezjak, A., Mehta, M. P., Liebmann,
J., Illidge, T., . . . Renschler, M. F. (2004). Neurocognitive function and progression in patients with brain metastases treated
with whole-brain radiation and motexafin gadolinium: Results
of a randomized phase III trial. Journal of Clinical Oncology,
22(1), 157–165. doi: 10.1200/JCO.2004.05.128
Meyers, C. A., & Wefel, J. S. (2003). The use of the mini-mental
state examination to assess cognitive functioning in cancer trials:
No ifs, ands, buts, or sensitivity. Journal of Clinical Oncology,
21(19), 3557–3558. doi: 10.1200/JCO.2003.07.080
Monaco, E. A., 3rd, Faraji, A. H., Berkowitz, O., Parry, P. V.,
Hadelsberg, U., Kano, H., . . . Lunsford, L. D. (2013). Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer.
Cancer, 119(1), 226–232. doi: 10.1002/cncr.27504
Monje, M. L., & Dietrich, J. (2012). Cognitive side effects of cancer
therapy demonstrate a functional role for adult neurogenesis.
Behavioural Brain Research, 227(2), 376–379. doi: 10.1016/j.
bbr.2011.05.012
Monje, M. L., Toda, H., & Palmer, T. D. (2003). Inflammatory
blockade restores adult hippocampal neurogenesis. Science,
302(5651), 1760–1765. doi: 10.1126/science.1088417
Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., &
Palmer, T. D. (2007). Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies.
Annals of Neurology, 62(5), 515–520. doi: 10.1002/ana.21214
Morris, P. G., Correa, D. D., Yahalom, J., Raizer, J. J., Schiff, D., Grant,
B., . . . Omuro, A. (2013). Rituximab, methotrexate, procarbazine,
and vincristine followed by consolidation reduced-dose whole-brain
radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: Final results and long-term outcome. Journal of Clinical
Oncology, 31(31), 3971–3979. doi: 10.1200/JCO.2013.50.4910
Nagesh, V., Tsien, C. I., Chenevert, T. L., Ross, B. D., Lawrence, T.
S., Junick, L., & Cao, Y. (2008). Radiation-induced changes in
normal-appearing white matter in patients with cerebral tumors:

A diffusion tensor imaging study. International Journal of Radiation Oncology Biology Physics, 70(4), 1002–1010. doi: 10.1016/j.
ijrobp.2007.08.020
Nelson, C. J., Lee, J. S., Gamboa, M. C., & Roth, A. J. (2008). Cognitive effects of hormone therapy in men with prostate cancer: A
review. Cancer, 113(5), 1097–1106. doi: 10.1002/cncr.23658
Neuwelt, E. A., Goldman, D. L., Dahlborg, S. A., Crossen, J.,
Ramsey, F., Roman-Goldstein, S., . . . Dana, B. (1991). Primary
CNS lymphoma treated with osmotic blood-brain barrier disruption: Prolonged survival and preservation of cognitive function. Journal of Clinical Oncology, 9(9), 1580–1590.
Noble, M., & Dietrich, J. (2002). Intersections between neurobiology
and oncology: Tumor origin, treatment and repair of treatmentassociated damage. Trends in Neurosciences, 25(2), 103–107.
Nordal, R. A., & Wong, C. S. (2005). Molecular targets in radiation-induced blood-brain barrier disruption. International Journal of Radiation Oncology Biology Physics, 62(1), 279–287. doi:
10.1016/j.ijrobp.2005.01.039
Peiffer, A. M., Leyrer, C. M., Greene-Schloesser, D. M., Shing, E.,
Kearns, W. T., Hinson, W. H., .  .  . Chan, M. D. (2013).


584

Denise D. Correa and James C. Root

Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline. Neurology, 80(8), 747–753. doi:
10.1212/WNL.0b013e318283bb0a
Pels, H., Schmidt-Wolf, I. G., Glasmacher, A., Schulz, H., Engert,
A., Diehl, V., . . . Schlegel, U. (2003). Primary central nervous
system lymphoma: Results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. Journal of Clinical Oncology, 21(24), 4489–4495. doi:
10.1200/JCO.2003.04.056
Platta, C. S., Khuntia, D., Mehta, M. P., & Suh, J. H. (2010). Current treatment strategies for brain metastasis and complications
from therapeutic techniques: A review of current literature.
American Journal of Clinical Oncology, 33(4), 398–407. doi:
10.1097/COC.0b013e318194f744
Pomykala, K. L., Ganz, P. A., Bower, J. E., Kwan, L., Castellon, S.

A., Mallam, S., . . . Silverman, D. H. (2013). The association
between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy
for breast cancer. Brain Imaging and Behavior, 7(4), 511–523. doi:
10.1007/s11682-013-9243-2
Poortmans, P. M., Kluin-Nelemans, H. C., Haaxma-Reiche, H.,
Van’t Veer, M., Hansen, M., Soubeyran, P., . . . Treatment of
Cancer Lymphoma, G. (2003). High-dose methotrexate-based
chemotherapy followed by consolidating radiotherapy in nonAIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer
Lymphoma Group Phase II Trial 20962. Journal of Clinical
Oncology, 21(24), 4483–4488. doi: 10.1200/JCO.2003.03.108
Poppelreuter, M., Weis, J., & Bartsch, H. H. (2009). Effects of specific neuropsychological training programs for breast cancer
patients after adjuvant chemotherapy. Journal of Psychosocial
Oncology, 27(2), 274–296. doi: 10.1080/07347330902776044
Poppelreuter, M., Weis, J., Kulz, A. K., Tucha, O., Lange, K. W., &
Bartsch, H. H. (2004). Cognitive dysfunction and subjective
complaints of cancer patients: A cross-sectional study in a cancer
rehabilitation centre. European Journal of Cancer, 40(1), 43–49.
Postma, T. J., Klein, M., Verstappen, C. C., Bromberg, J. E., Swennen, M., Langendijk, J. A., . . . Heimans, J. J. (2002). Radiotherapy-induced cerebral abnormalities in patients with low-grade
glioma. Neurology, 59(1), 121–123.
Postma, T. J., van Groeningen, C. J., Witjes, R. J., Weerts, J. G.,
Kralendonk, J. H., & Heimans, J. J. (1998). Neurotoxicity of
combination chemotherapy with procarbazine, CCNU and vincristine (PCV) for recurrent glioma. Journal of Neuro-Oncology,
38(1), 69–75.
Quesnel, C., Savard, J., & Ivers, H. (2009). Cognitive impairments
associated with breast cancer treatments: Results from a longitudinal study. Breast Cancer Research and Treatment, 116(1), 113–
123. doi: 10.1007/s10549-008-0114-2
Raber, J., Rola, R., LeFevour, A., Morhardt, D., Curley, J., Mizumatsu, S., . . . Fike, J. R. (2004). Radiation-induced cognitive
impairments are associated with changes in indicators of hippocampal neurogenesis. Radiation Research, 162(1), 39–47.
Reardon, D. A., Galanis, E., DeGroot, J. F., Cloughesy, T. F.,
Wefel, J. S., Lamborn, K. R., . . . Wen, P. Y. (2011). Clinical trial

end points for high-grade glioma: The evolving landscape. Neuro
Oncology, 13(3), 353–361. doi: 10.1093/neuonc/noq203
Regine, W. F., Schmitt, F. A., Scott, C. B., Dearth, C., Patchell, R.
A., Nichols, R. C., Jr., . . . Mehta, M. P. (2004). Feasibility of
neurocognitive outcome evaluations in patients with brain

metastases in a multi-institutional cooperative group setting:
Results of Radiation Therapy Oncology Group trial BR-0018.
International Journal of Radiation Oncology Biology Physics,
58(5), 1346–1352. doi: 10.1016/j.ijrobp.2003.09.023
Reid, L. M., & Maclullich, A. M. (2006). Subjective memory complaints and cognitive impairment in older people. Dementia and Geriatric Cognitive Disorders, 22(5–6), 471–485. doi: 10.1159/000096295
Reuter-Lorenz, P. A., & Cimprich, B. (2013). Cognitive function
and breast cancer: Promise and potential insights from functional brain imaging. Breast Cancer Research and Treatment,
137(1), 33–43. doi: 10.1007/s10549-012-2266-3
Rubenstein, J. L., Ferreri, A. J., & Pittaluga, S. (2008). Primary
lymphoma of the central nervous system: Epidemiology, pathology and current approaches to diagnosis, prognosis and treatment. Leuk Lymphoma, 49(Supplement), 43–51.
Rubenstein, J. L., Hsi, E. D., Johnson, J. L., Jung, S. H., Nakashima,
M. O., Grant, B., . . . Kaplan, L. D. (2013). Intensive chemotherapy and immunotherapy in patients with newly diagnosed
primary CNS lymphoma: CALGB 50202 (Alliance 50202).
Journal of Clinical Oncology, 31(25), 3061–3068. doi: 10.1200/
JCO.2012.46.9957
Rzeski, W., Pruskil, S., Macke, A., Felderhoff-Mueser, U., Reiher,
A. K., Hoerster, F., .  .  . Ikonomidou, C. (2004). Anticancer
agents are potent neurotoxins in vitro and in vivo. Annals of Neurology, 56(3), 351–360. doi: 10.1002/ana.20185
Salander, P., Karlsson, T., Bergenheim, T., & Henriksson, R. (1995).
Long-term memory deficits in patients with malignant gliomas.
Journal of Neuro-Oncology, 25(3), 227–238.
Schagen, S. B., Boogerd, W., Muller, M. J., Huinink, W. T., Moonen,
L., Meinhardt, W., & Van Dam, F. S. (2008). Cognitive complaints and cognitive impairment following BEP chemotherapy
in patients with testicular cancer. Acta Oncologica, 47(1), 63–70.

doi: 10.1080/02841860701518058
Schagen, S. B., Das, E., & van Dam, F. S. (2009). The influence of
priming and pre-existing knowledge of chemotherapy-associated
cognitive complaints on the reporting of such complaints in
breast cancer patients. Psychooncology, 18(6), 674–678. doi:
10.1002/pon.1454
Schagen, S. B., Muller, M. J., Boogerd, W., Mellenbergh, G. J., &
van Dam, F. S. (2006). Change in cognitive function after chemotherapy: A prospective longitudinal study in breast cancer
patients. Journal of the National Cancer Institute, 98(23), 1742–
1745. doi: 98/23/1742 [pii] 10.1093/jnci/djj470
Schagen, S. B., van Dam, F. S., Muller, M. J., Boogerd, W., Lindeboom, J., & Bruning, P. F. (1999). Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer,
85 (3), 640–650. doi: 10.1002/(SICI)1097-0142(19990201)
85:3<640::AID-CNCR14>3.0.CO;2-G [pii]
Scheibel, R. S., Meyers, C. A., & Levin, V. A. (1996). Cognitive
dysfunction following surgery for intracerebral glioma: Influence
of histopathology, lesion location, and treatment. Journal of
Neuro-Oncology, 30(1), 61–69.
Scherling, C., Collins, B., Mackenzie, J., Bielajew, C., & Smith, A.
(2011). Pre-chemotherapy differences in visuospatial working
memory in breast cancer patients compared to controls: An
FMRI study. Frontiers in Human Neuroscience, 5, 122. doi:
10.3389/fnhum.2011.00122
Scherwath, A., Mehnert, A., Schleimer, B., Schirmer, L., Fehlauer,
F., Kreienberg, R., .  .  . Koch, U. (2006). Neuropsychological
function in high-risk breast cancer survivors after stem-cell