Brain Tumor Symptoms As Antecedents To Uncertainty: An Integrative Review

CLINICAL SCHOLARSHIP
Brain Tumor Symptoms as Antecedents to Uncertainty:

An Integrative Review
Jennifer Cahill, MS, RN1 , Geri LoBiondo-Wood, PhD, RN, FAAN2 , Nancy Bergstrom PhD, RN, FAAN3 ,
& Terri Armstrong, PhD, ANP-BC4
1 Mu, Doctoral Student, Doctoral Program in Nursing, University of Texas, School of Nursing at Houston, Houston, TX
2 Upsilon, Associate Professor and Director of Nursing Research and Evidence-Based Practice, University of Texas, M.D. Anderson Cancer Center,
Houston, TX
3 Zeta Pi, Professor and Director of Aging Research, Center on Aging, University of Texas, School of Nursing at Houston, TX
4 Zeta Pi, Associate Professor, University of Texas, M.D. Anderson Cancer Center, and Department of Integrative Care, University of Texas, School of
Nursing at Houston, both in Huston, TX
Key words
Symptoms, primary brain tumors, metastatic
brain tumors, uncertainty
Correspondence
Jennifer Cahill, University of Texas, School of
Nursing at Houston, 6901 Bertner Ave.,
Houston, TX 77030. E-mail:
jennifer.e.cahill@uth.tmc.edu
Accepted March 25, 2012
doi: 10.1111/j.1547-5069.2012.01445.x
Abstract
Purpose: Uncertainty is a common experience within human cancer. For
brain tumor patients, irregular symptom pattern and presentation may promote uncertainties about treatment response, prognosis, and life quality. We
sought to identify the somatic symptom experience associated with primary
and secondary brain tumors and the potential impact on illness-related uncertainty.
Methods: An integrative literature search of Medline and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed. Symptom data were excerpted into tables and reviewed critically against the broader
uncertainty-focused oncology literature.
Results: Twenty-one studies investigated a diverse range of brain tumor
symptoms that persist through the now-expanding, post-treatment survival.
While symptoms such as fatigue were common, antecedents and patterns were
poorly characterized and inconsistent between and within categories of tumor.
Conclusions and Implications: Symptom investigation is an emerging and
rapidly developing area of neuro-oncology. The extent to which symptoms are
familiar, predictable, and understandable can mitigate uncertainty. The unstable nature of symptoms across the trajectory of a brain tumor may be a
significant corollary to illness-related uncertainty.
Clinical Relevance: Because the majority of brain tumor patients cannot be
cured of their cancer, understanding the symptom expanse and potential to
promote uncertainty could inform alternative nursing strategies to reduce anxiety and distress, and to preserve life quality where cure is often unattainable.
Despite significant advances in treatment and survival,

there remains substantial symptom burden associated
with the diagnosis of a brain tumor. Subtle neurologic
disability is often present, and for advanced disease, major consequences can include progressive functional impairment, cognitive decline, and death. Treatment of a
brain tumor is generally palliative; surgical tumor debulking, radiotherapy, and chemotherapy are used alone and
in combination to prolong life, decelerate neurologic impairment, and alleviate symptoms. However, many therapies consequently elicit severe secondary symptoms that
Journal of Nursing Scholarship, 2012; 44:2, 145155.

C 2012 Sigma Theta Tau International
can degrade quality of life (QoL; Lovely, 2004; Lovely,

Miaskowski, & Dodd, 1999). These symptoms are important to balance against absolute survival and other clinical
benefits of treatment.
Symptoms
Symptoms and Brain Turmors
The symptom experience for any individual patient is
difficult to predict. Primary brain tumors (PBTs) evolve
from and within central nervous tissue and are thus
145
Brain Tumor Symptoms and Uncertainty
distinct from the more prevalent metastatic (secondary)

brain tumors (METs). Symptoms associated with PBTs
and METs may differ according to the biology of infiltrative invasive disease in the former, and the collateral
presence of systemic disease in the latter. Moreover, despite standard treatments, symptoms vary between and
within categories of tumor as a function of grade, size, location, and histology (Lovely, 2004), in addition to complex anatomical and functional variants, such as speech
lateralization. Throughout the disease, symptoms may
wax and wane, disappear completely, or emerge latently,
limiting reliable interpretation of symptoms as evidence
for stabilization, remission, or recurrence of the tumor.
Symptoms and Uncertainty

The Theory of Uncertainty in Illness (Mishel, 1988)
posits that patients unable to infer symptom-based patterns have difficulty predicting outcomes, which promotes a state of uncertainty (Clayton, Mishel, & Belyea,
2006). Accordingly, the inconsistent and ambiguous nature of symptoms likely engenders uncertainty in brain
tumor patients. Although well characterized in other oncology samples (e.g., breast, prostate, and gynecologic
cancers), uncertainty has not yet been evaluated in brain
tumor patients using the principal scale developed by
Mishel (1981). Notably, however, a specific uncertainty
of future (derived from a single-item on a brain-tumor
QoL scale) is a supportive and preliminary finding significantly associated with symptoms of deteriorating neurologic status (Osoba et al., 1997; Taphoorn et al., 2010).
Because uncertainty confers significant risk for negative
outcomes, including clinically relevant distress (Clayton,
Mishel, & Belyea, 2006) and reduced QoL (Sammarco
& Konecny, 2008), it may be an important psychosocial
corollary to symptom management in brain tumor patients.
Exploring Symptoms as Potential Antecedents

of Uncertainty
Mishel (1988) framed the progenitors of uncertainty
according to three subclassifications: stimuli frame, cognitive capacity, and structure providers. The pattern of
somatic symptoms is included under the stimuli frame
(Mishel, 1988) and is the specific focus of this article,
given the preliminary correlations between neurologic
symptoms and future uncertainty (Osoba et al., 1997;
Taphoorn et al., 2010). Furthermore, irregular physical symptom experience has been presented as one of
the strongest predictors of uncertainty in other cancers (Mishel & Braden, 1987). Therefore, utilizing the
methodological approach outlined by Whittemore and
146
Cahill et al.
Knafl (2005), the purpose of this integrative review was

to synthesize the somatic symptom experience reported
for brain tumors, in order to identify aspects that were potential correlates of uncertainty. While many uncertainties for patients with a brain tumor cannot be resolved,
identification and integration of uncertainty within a
nursing-based, symptom-management framework could
inform leading strategies to reduce anxiety and distress,
and to preserve QoL when cure is often unattainable.
Methods
A search of Medline and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was executed
using the strategy: AB symptom and AB (cancer or
neoplasm) and AB brain. The search parameters included quantitative, qualitative, or mixed methods research, published in an English-language, peer-reviewed
journal from January 1, 2004, to July 1, 2011. Time restrictions reflect the most recent standardizations of treatment for METs (whole brain radiation therapy [WBRT]
and stereotactic radiosurgery; see Andrews et al., 2004)
and the major subgroup of malignant PBT (radiotherapy plus concomitant and adjuvant temozolomide for
glioblastoma; see Stupp et al., 2005). Titles and abstracts
were assessed for relevance. Studies examining subjects
at least 18 years old with a PBT or MET were considered.
Articles that evaluated somatic symptoms (e.g., fatigue,
headache) at any stage of disease were included. Studies
that exclusively measured psychosocial or neuropsychiatric symptoms (e.g., anxiety, depression) or neurocognitive function, (e.g., memory, processing speed) were
excluded. Position papers, reviews, abstracts, and unpublished dissertations were discarded. Reference lists of
pertinent publications were scanned for supplementary
articles.
Results
Six-hundred-one publications were retrieved, and 21
articles met inclusion criteria (Table 1). The majority
of studies were descriptive, utilizing cross-sectional or
repeated measures survey designs. Sample sizes ranged
from 54 to 490 subjects, with larger samples typically representing secondary analyses of combined clinical trial
data. Studies broadly spanned the diagnostic histological spectrum, including heterogeneous pooling of different grade (IIV) PBTs (Armstrong et al., 2006) and subclasses of lower-grade glioma such as ependymomas and
others (Armstrong, Vera-Bolanos, & Gilbert, 2011; Struik
et al., 2009), high-grade gliomas including grade IV
glioblastomas (Bosma et al., 2009; Fox, Lyon, & Farace,


Prediagnosis
Mixed: pretreatment &
others
Mixed disease states
Mixed treatment states
Cross-sectional, survey to
determine characteristics
& co-occurring symptoms
of fatigue
Retrospective chart review Ependymomas in United

to evaluate & characterize States (n = 123)
ependymomas
describe clinical course of
ependymomaa
Armstrong, Cron, et al.

(2010)
Inter-disciplinary
Armstrong, Vera-Bolanos,
et al. (2010)
Inter-disciplinary
& Gilbert (2011)
Inter-disciplinary
Ependymomas in United
States (n = 118)
Newly diagnosed or
recurrent tumors
Active treatment
Multiple
MDASI-BT
Multiple
Investigator-derived
inventory
MDASI-BT
Multiple
MDASI-BT
Multiple
Postdiagnosis
Active & post-treatment
Metastases from
melanoma, lung, breast &
others in United States
(n = 124)
Primary tumors in United
States (n = 201)
evaluate MDASI-BT in
metastases
Armstrong et al. (2009)

Inter-disciplinary
Multiple
MDASI-BT
Postdiagnosis
Active & post-treatment
Primary tumors in United

States (n = 201)
evaluate validity &
reliability of the MDASI-BT
Armstrong et al. (2006)

Inter-disciplinary
Headache & others

inventory
Prediagnosis
Pretreatment
Lung, breast, colorectal,

& others with new or
changed headache in
Greece (n = 54)
Prospective, cohort study

of symptoms to predict
brain metastases
Argyriou et al. (2006)

Inter-disciplinary
Multiple
inventory
End stage
Post-treatment palliation
Symptoms & inventory
Malignant primary tumors

in England (n = 70)
Retrospective case review

of symptoms
Status
Arber et al. (2010)

Nursing
Sample & setting
Purpose & design
Article & discipline
Table 1. Symptom Findings in Primary and Metastatic Brain Tumors
(4%), headaches (4%), extrapyrimadal (3%), seizures (3%),

tiredness (1%)
r 79% with metastases had headache 8 weeks
r 58% had co-occurring headache symptoms: emesis,
dizziness, & gait instability, alone or in combination
r Predictive of metastases (p .05): headache of specic
type, nystagmus, coordination problems, emesis,
diplopia, papiledema, gait instability, babinski reex,
dizziness
r Most frequent & severe symptom: fatigue
r Moderate to severe: drowsiness, sleepiness, sleep, pain,
disturbance, difculty remembering, distress,
dry mouth
r Least frequent or severe: SOB, vomiting, seizures,
seizure change
r Most severe: fatigue, sleep disturbance, drowsiness,
distress, dry mouth
r Least severe: seizures, nausea, vomiting, difculty
remembering, understanding, speaking, concentrating
r Predictors of fatigue: poor performance status, female
gender, disease status
r Disease status predicted fatigue severity in females
r Antidepressant use, opioid use, performance status
predicted fatigue severity in males
r Co-occurring symptoms of moderate to severe fatigue
(p .002): pain, distress, drowsiness, weakness, &
overall symptom severity or interference
r Presenting symptoms prior to diagnosis: pain (70%),
mental status changes (50%), coordination issues (45%),
nausea or vomiting (30%), seizures (15%), weakness
(13%), sensory (12%), emotional problems (13%)
r Prediagnosis: headache (52%), visual problems (46%),
nausea or vomiting (39%), weakness (33%), numbness or
tingling (33%) with symptoms >6 months before clinical
presentation in 37%
r 56% had 1 or more symptoms; 10% had 4+

r Signicant: hemiparesis (17%); cognitive problems (16%)
r Least reported: nausea or vomiting (4%), incontinence
Symptom-specic ndings
Cahill et al.
147
148
Cross-sectional, pooled
survey to determine QOL
& association to outcome
Repeated measures
survey to assess WBRT
symptoms
Chow et al. (2005)

Radiation oncology
Repeated measures
survey to compare QOL,
determine QOL effect on
recurrence & survival
Bosma et al. (2009)

Inter-disciplinary
Brown et al. (2006)

Inter-disciplinary
Cross-sectional, pooled
survey data to evaluate
prediction of progression
on MRI by symptom
severity & interference
Purpose & design
Gning, et al. (2011)
Inter-disciplinary
Table 1 Continued
Fatigue
SDS
Multiple
ESAS
Postdiagnosis
Mixed: postresection &
postradiation
Postdiagnosis
Palliative with WBRT
Grade 3 & 4 gliomas in

United States (n = 220)
Brain metastases from

lung, breast, & others in
Canada (n = 170)
Multiple
Postdiagnosis
Mixed treatment, including BCM-20
experimental therapies
High-grade glioma
survivors in the
Netherlands (n = 68)
Multiple
MDASI-BT
Postdiagnosis
Mixed: active or
post-treatment of initial
disease
Status
Primary brain tumors in

Sample & setting
fatigue (44%), numbness or tingling (39%), pain (36%),

disturbed sleep (34%), vision (25%), concentration (25%),
weakness (19%), irritability (19%), difculty speaking
(19%), understanding (17%)
r Lowest severity: vomiting, seizures, nausea, SOB
r Most frequent, moderate-to-severe: pain, fatigue,
sleepiness, distress, difculty remembering,
drowsiness with 20% reporting moderate symptom
interference
r Severity & activity interference (general activity, work, &
walking) associated with progression on MRI
(univariate analysis)
r Activity interference more predictive of recurrence than
KPS, age, extent of resection.
r Prominent symptoms of long-term survivors: headache,
communication decits, drowsiness, motor dysfunction
r Prominent symptoms of short-term survivors:
headache, communication decit, visual disorder,
motor dysfunction, drowsiness
r Symptoms generally worsened over time for short-term
survivors & stabilized for long-term survivors
r Fatigue associated with hemisphere: R > L (p < .05)
r Prior radiotherapy associated with fatigue (p < .05)
r Poor performance status associated with debilitating
fatigue (p < .05)
r Less fatigue associated with survival (p < .05)
r Most severe symptom: fatigue
r Fatigue, drowsiness, poor appetite more severe
post-WBRT
r No symptoms improved after WBRT
r Recurrence: numbness or tingling (25%), headache (25%)

r Current, severe or moderate-to-severe symptoms:
weakness (33%), seizures (12%)
r Treatment-related symptoms (primarily surgery):

Cahill et al.

Repeated measures
survey to explore
symptom clustersb
Repeated measures
survey to examine
symptoms in metastases
treated by WBRT
Retrospective chart review Primary or metastatic

tumors in United States (n
to evaluate seizures as a
= 147)
presenting symptom of
tumor
Gleason et al. (2007)

Radiation oncology

Hird et al. (2010)

Radiation oncology
Lynam et al. (2007)

Inter-disciplinary
PostdiagnosisMixed: pre- Multiple FACT

& post-therapy with partial FACT-BrCESD
or WBRT study drug
Multiple
inventory
Seizure
inventory
Postdiagnosis
Prediagnosis
Pretreatment
Metastatic or primary
tumors in United States (n
= 66)

Canada (n = 129)
Multiple COGMOS; BPI;

BFI; GSDS;
HADS-Depression
Postdiagnosis
Post-treatment: surgery &
chemoradiation
Glioblastomas,anaplastic
astrocytomas,
oligo-astrocytomas in
Cross-sectional survey to
examine co-occurring
symptoms, QOL, &
functional status in
high-grade glioma
Fox et al. (2007)

Nursing
Multiple ESAS
Postdiagnosis
Status

Canada (n = 170)
Repeated measures
survey to examine
symptom clusters during
WBRT
Chow et al. (2008)

Radiation oncology
Sample & setting
Purpose & design
Table 1 Continued
(37% of variance); Cluster 2 = anxiety, depression (12%

of variance); Cluster 3 = nausea, poor appetite & poor
sense of well-being (13% of variance).
r Most prevalent & severe: sleep disturbance (100%)
r Least prevalent: pain (58%).
r 2 Clusters: depression, fatigue, sleep disturbance,
cognitive impairment, pain (62% of functional status
variance); depression, fatigue, sleep disturbance,
cognitive impairment (29% of QOL variance)
r Correlations: depression, pain not correlated; pain, QOL
not correlated
r Symptoms prevalent in > 20%: lack of energy, sleep
problems, nervousness, sadness, difculty
remembering, frustration, vision problems, word
nding difculties, reading difculties, problems
concentrating, writing difculties, depression
r 2 Clusters: language (difculty reading, writing, word
nding); mood (sadness, anxiety, depressed mood)
r 3 Clusters: trouble concentrating, decreased alertness,
confusion, imbalance problems, memory loss,
weakness, fatigue, vision problems, problems with
smell, hearing, or tingling (23% of variance); nausea,
vomiting, headache, dizziness (11% of variance);
seizures, numbness, speech difculty, personality
change, (8% of variance).
r Seizure presenting symptom: 38% primary, 20% of
metastatic tumors
r Oligodendrogliomas, grade 2 astrocytomas associated
with seizures at presentation
r 58% primary, 34% metastatic tumors had seizure at
some point in disease
r Clusters: Cluster 1 = fatigue, drowsiness, SOB, pain
(88.1%), drowsiness (82.2%) anxiety (82.1%).
r Most prevalent: fatigue (91.7%), poor well-being sense
drowsiness, poor appetite
r Most severe: fatigue, poor well-being sense, anxiety,
Cahill et al.
149
150
Repeated measures
survey to explore QOL,
symptom distress,
functional status, &
depression

Repeated measures
survey to prospectively
examine QOL & symptoms Canada (n = 129)
in brain metastases before
& after WBRT
Tsay et al. (2012)

Nursing
Wong et al. (2009)

Radiation oncology
Benign tumors in Taiwan

(n = 58)
Multiple
inventory
Postdiagnosis Palliative
with WBRT
Fatigue
CIS
Postdiagnosis
Post-treatment
Multiple
MDASI-T
HADS
Multiple
BCM-20
Newly diagnosed
Pretreatment
Prediagnosis Mixed: prior

to & 1 month
postresection
Multiple
BCM-20
Newly diagnosed
Pretreatment
Status
dysfunction, seizures, lower extremity weakness

predictive for survival (univariate analysis)
r Final model: cognitive functioning, global health status,
social functioning predictive of survival
r Emotional functioning, communication decit, future
uncertainty, weakness of legs, predictive of survival
(univariate analysis)
r Unable to achieve nal predictive model
r 39% reported severe fatigue
r Fatigue severity not related to gender, radiation
treatment
r Fatigue associated with anticonvulsant use
r Severe fatigue correlated with low motivation, low
activity, problems concentrating
r Mean symptom distress score: 84.74 (SD 32.27, range
5143) prior to surgery & 40.76 (SD 13.28, range 17
63) 1 month after surgical discharge
r QOL variance due to symptom distress: 80.2% prior to
surgical resection, 27.1% at 1 month after surgical
discharge
r Most frequent: headaches, weakness, imbalance,
fatigue
r Infrequent: seizures, speech difculty, vomiting
r No symptom changes except for fatigue & headache
r After WBRT: 57% had more fatigue, 25% had less fatigue
& 41% less severe headaches
r Severe vomiting correlated with decreased survival
r QOL domains did not improve following WBRT, except
for daily living & health
r Bladder control, communication decit, motor
a
Findings reported for intracranial lesions only. b Secondary analysis of randomized, controlled trial.
BCM-20 = Brain Cancer Module-20 item; BFI = Brief Fatigue Inventory; BPI = Brief Pain Inventory; CIS = Checklist Individual Strength; COGMOS = Cognitive Functioning Subscale of Medical Outcomes
Scale; HADS-Depression = Depression Subscale of Hospital Anxiety & Depression Scale; ESAS = Edmonton Symptom Assessment Scale; FACT = Functional Assessment of Cancer Therapy; FACT-Br =
Functional Assessment of Cancer TherapyBrain tumor; GSDS = General Sleep Disturbance Scale; HADS = Hospital Anxiety & Depression Scale; KPS = Karnofsky Performance Status; MDASI-BT = M.D.
Anderson Symptom Inventory for Brain Tumor; MDASI-T = Taiwanese version; QOL = quality of life; SOB = shortness of breath; SDS = Symptom Distress Scale; WBRT = whole brain radiation therapy.
Struik et al. (2009)

Inter-disciplinary
Anaplastic
oligo-dendrogliomas
throughout Europe
(n = 247)
Long-term survivors of
low-grade glioma in the
Netherlands (n = 54)
explore baseline QOL,
symptoms to predict
survivalb
assess fatigue severity &
prevalence in survivors
Mauer, Taphoorn, et al.

(2007) Inter-disciplinary
Glioblastomas throughout
Europe (n = 490)
Sample & setting
explore baseline QOL,
symptoms to predict
survivalb
Purpose & design
Mauer, Stupp, et al. (2007)

Inter-disciplinary
Table 1 Continued

Cahill et al.

Cahill et al.
2007), and METs predominantly from lung, breast, and

gastrointestinal and genitourinary cancers (Argyriou et
al., 2006; Chow et al., 2005). While most focused on PBTs
or METs separately, two articles analyzed an integrated
sample (Gleason et al., 2007; Lynam et al., 2007).
Findings chiefly comprise symptom type and severity
that vary according to measurement (Table 1), with the
majority utilizing multisymptom, self-report scales. However, only a subset of instruments was psychometrically
validated and reliable for brain tumor patients. A few
studies were restricted to single-symptom measurement,
especially fatigue (Armstrong, Cron, Bolanos, Gilbert, &
Kang, 2010; Brown et al., 2006). A minority addressed
symptom clusters (Fox, Lyon, & Farace, 2007) and some
evaluated effects on patient sensitive outcomes such as
QoL (Mauer, Stupp, et al., 2007). Studies revealed symptoms across various time points, with a majority reporting
on postdiagnostic phases of active treatment or watchful waiting. Two studies reported on long-term survivors
(Struik et al., 2009; Bosma et al., 2009), and a single study
evaluated symptoms at end stage for PBT patients receiving palliative or hospice care (Arber, Faithfull, Plaskota,
Lucas, & de Vries, 2010). The bulk of MET studies included palliative therapy with WBRT (Chow et al., 2005,
2008; Hird et al., 2010; Wong et al., 2009) or partial radiotherapy (Gleason et al., 2007).
Major Symptom-related Findings for Brain

Tumor Patients
Fatigue. When evaluated, fatigue was often rated
the most frequent and severe symptom, except at endstage PBT (Arber et al., 2010). Chow et al. (2005) found
a statistically significant worsening of fatigue following
WBRT in METs; these findings were replicated by Wong
et al. (2009), who reported that 57% experienced more
severe fatigue after WBRT. Interestingly, a correlation between fatigue and radiation was not supported for PBT
patients in a mixed sample (Armstrong, Cron, et al.,
2010) or low-grade glioma survivors (Struik et al., 2009),
a divergent finding from earlier evaluations (Lovely
et al., 1999; Faithfull & Brada 1998). Fatigue is correlated
with other treatment variables, including anticonvulsants
(Struik et al., 2009) and antidepressant and opioid use in
males (Armstrong, Cron, et al., 2010).
Outcomes such as QoL (Brown et al., 2006; Fox
et al., 2007), performance status (Armstrong, Cron, et al.,
2010; Brown et al., 2006), survival (Brown et al., 2006)
and disease status (Armstrong, Cron, et al., 2010) correlated with fatigue, although interpretation of these results is inherently complex. Correlative symptoms of fatigue included sleep disturbance (Fox et al., 2007), pain
(Armstrong, Cron, et al., 2010; Fox et al., 2007), distress

(Armstrong, Cron, et al., 2010), drowsiness (Armstrong,

Cron, et al., 2010; Chow et al., 2005, 2008), problems
concentrating (Struik et al., 2009), cognitive status (Fox
et al., 2007), and depression (Chow et al., 2008; Fox
et al., 2007). Fatigue was a prominent cluster member
with other symptoms (Chow et al., 2008; Hird et al.,
2010), most notably in two distinct clusters reported by
Fox et al. (2007) that predict functional status (depression, fatigue, sleep disturbance, cognitive impairment,
pain) and QoL (depression, fatigue, sleep disturbance,
cognitive impairment).
Developing focus on survivorship demonstrated that
severe fatigue may persist in low-grade glioma patients,
despite completion of treatment 8 to 29 years previously
(Struik et al., 2009). Thus, the pervasive finding of fatigue and intercorrelation with important outcomes and
other symptoms across the diversity of studies signify its
prominence as the most prevalent and perhaps clinically
important symptom of a brain tumor.
Headache and pain. Multiple studies reported

presence of pain or headache as a characteristic symptom
at diagnosis for PBTs (Armstrong, Vera-Bolanos, Bekele,
Aldape, & Gilbert, 2010; Armstrong, Vera-Bolanos, &
Gilbert, 2011) and headache was the strongest independent predictor of METs (Argyriou et al., 2006). Moderate to severe pain persists throughout the active and
post-treatment stages of PBTs (Armstrong, Vera-Bolanos,
& Gilbert 2011; Armstrong, Vera-Bolanos, Gning, et al.,
2011), but was less prevalent in survivorship (Fox et al.,
2007). For greater than half of METs receiving WBRT,
pain was present, though not usually severe, at baseline and through treatment and follow-up (Chow et al.,
2005; Chow et al., 2008; Hird et al., 2010; Wong et al.,
2009). Wong et al. (2009) additionally report improved
headache severity scores from baseline following WBRT.
Pain is often correlated to fatigue (Armstrong, Cron,
et al., 2010; Fox et al., 2007). The extent of pain reporting across samples signifies it as dominant symptom associated with the experience of a brain tumor.
Nausea and vomiting. Vomiting was strongly predictive of METs in patients with various primary cancers (Argyriou et al., 2006). Following diagnosis, nausea
and vomiting (N/V) were described as present but not severe in METs, with stable mean severity scores throughout WBRT (Chow et al., 2005; Wong et al., 2009). In a
sample of 129 MET patients undergoing WBRT, 75% did
not report N/V. As reported in other cancer samples, nausea typically clustered tightly with vomiting (Chow et al.,
2008; Hird et al., 2010) and poor appetite (Chow et al.,
2008).
151
N/V were common at diagnosis for 30% to 40% of

PBT (ependymoma) patients (Armstrong, Vera-Bolanos
et al., 2010; Armstrong, Vera-Bolanos, & Gilbert, 2011).
However, following initial treatment with surgical resection (with or without radiation and chemotherapy), N/V
were not listed as moderate-to-severe symptoms (Armstrong, Vera-Bolanos, & Gilbert, 2011). Similarly, N/V
were among the least severe symptoms in PBT patients
of mixed tumor grade and diverse treatment states (Armstrong, Vera-Bolanos, & Gilbert, 2011). Lacking data on
concomitant prophylactic therapies, the general conclusion is that N/V may be less pronounced following treatment or, alternatively, very well-controlled with medication following diagnosis.
Neurologic and mental status symptoms. As

expected, neurologic symptoms were common. Dizziness was reported for METs (Argyriou et al., 2006; Hird
et al., 2010), and weakness, gait instability, coordination,
or balance symptoms were broadly associated with all tumors (Argyriou et al., 2006; Wong et al., 2009). Sensory
problems with vision, hearing, or smelling were identified
for all tumors (Argyriou et al., 2006; Armstrong, VeraBolanos, et al., 2010; Hird et al., 2010), with visual effects especially prominent among ependymoma patients
(Armstrong, Vera-Bolanos, & Gilbert, 2011). Numbness
and tingling were reported at a moderate to high severity
in 15% of a heterogeneous sample of PBTs (Armstrong,
Vera-Bolanos, Gning, et al., 2011) and 39% of ependymomas (Armstrong, Vera-Bolanos, & Gilbert, 2011).
Symptoms that alter awareness and consciousness
were common at presentation of PBT, specifically,
ependymoma (Armstrong, Vera-Bolanos, et al., 2010).
Mild to moderately severe decreased alertness was additionally reported for approximately 30% of MET patients undergoing WBRT (Hird et al., 2010). Drowsiness
was one of the most severe and prevalent (82%) symptoms (Chow et al., 2008) for METs, typically increasing
in severity after WBRT (Chow et al., 2005). For PBT patients, drowsiness was a regular feature of fatigue (Armstrong, Cron, et al., 2010) and was frequently identified
as moderate to severe (Armstrong, Vera-Bolanos, Gning,
et al., 2011).
Seizure. Seizure was the least reported symptom
across studies, primarily manifesting at diagnosis. Seizure
was the presenting symptom in 15% of PBTs (ependymoma; Armstrong, Vera-Bolanos, et al. 2010) and occurred in 12% following surgical resection (Armstrong,
Vera-Bolanos, & Gilbert, 2011). However, seizures were
not identified as a significant symptom at all other
stages of the disease (Armstrong, Vera-Bolanos, & Gilbert,
2011). Similarly, seizure was the presenting symptom in
152
Cahill et al.
38% of mixed PBTs (Lynam et al., 2007) but was one

of the most infrequent and least severe symptoms reported for a more treatment-diverse group of PBTs (Armstrong, Vera-Bolanos, Gning, et al., 2011). Congruently,
seizure may be a frequent and severe symptom in 20%
of primary cancer patients at the time of MET diagnosis
(Lynam et al., 2007). Nevertheless, during palliation with
WBRT, nearly 90% of these patients reported no seizure
activity (Wong et al., 2009). Although uncharacterized
further, differences in seizure frequency from time of diagnosis likely reflect current standards of anticonvulsant
prophylaxis.
Symptom distress and interference. Few studies evaluated symptom distress and interference as separate concepts to symptom frequency and severity; this
is likely a measurement limitation. Tsay, Chang, Yates,
Lin, and Liang (2012) explored the relationship between
symptom distress and QoL in a prospective cohort of 58
patients with a presumptive benign brain tumor. Symptom distress independently accounted for 80.2% of the
variance in QoL prior to surgery and 27.1% of the variance in QoL at 1 month following hospital discharge.
Armstrong, Vera-Bolanos, Gning et al. (2011) examined
whether symptom interference could predict tumor progression or recurrence on MRI in PBTs. While univariate
analyses demonstrated association between symptom interference and MRI results, the cross-sectional study design limits the strength of the prediction model. While
still preliminary, these findings may indicate that the
amount of symptom interference encountered during the
pursuit of general activity directly corresponds to disease
status, providing a potential benchmark to assess treatment response.
Discussion
Symptom reports are highly dependent on the instruments and methods (e.g., chart review versus self-report)
used to acquire the data. Notably, only a few instruments were symptom specific to brain tumors (Brain
Cancer Module-20 item, M.D. Anderson Symptom Inventory for Brain Tumor, and Functional Assessment of
Cancer TherapyBrain tumor), and the constituent items
and descriptors varied widely even between these. Consistent application of brain tumorspecific scales to gauge
symptoms would better facilitate study comparison and
integration of findings.
Despite the expanse and incongruity of symptom measurement, however, generalities regarding the nature of
symptoms emerge that can be compared with known correlates of symptom attributes and uncertainty in other
cancers. Perhaps the strongest theme across studies was

Cahill et al.
the prominence and severity of fatigue, altered mental

status, and neurologic symptoms for all brain tumor patients, regardless of tumor type or treatment state. In particular, fatigue has been strongly correlated with uncertainty during treatment and in the post-treatment survival period of other cancers (Clayton, Mishel, & Belyea,
2006; Mast, 1998). While uncertainty generally decreases
with increasing experience of the cancer course, the occurrence of new or exacerbating symptoms, especially in
the post-treatment survival period, can promote a state
of uncertainty (Clayton et al., 2006). Preliminary support for this finding in short-term survivors of high-grade
glioma was noted in the study by Bosma et al. (2009),
which showed a significant association between worsening symptom severity and the degree of future uncertainty. In contrast, as symptoms stabilized for longterm survivors, future uncertainty decreased steadily over
time.
Although limited studies explored symptom distress
and interference in brain tumor patients, there is preliminary evidence that most patients report multiple symptoms and that both distress and interference may influence QoL and performance status, and may be predictive
of recurrence, suggesting a mediating effect on patientsensitive outcomes. Greater symptom distress and an increased number of symptoms have consistently correlated with higher levels of uncertainty in other cancer
patients throughout the illness trajectory (Mast, 1998;
Porter et al., 2006). This is congruent with findings in patients with other solid tumors, such as ovarian and breast
cancer, in which symptoms and uncertainty are associated with increased anxiety and poorer QoL (McCorkle
et al., 2009). The relationship between symptom frequency and distress and uncertainty and the impact on
patient sensitive outcomes requires further investigation.
Brain tumor patients report a diverse range of somatic
symptoms that can be experienced inconsistently across
tumor types and treatment phases. Symptoms greatly
varied in frequency and in combination, with fluctuating
severities and indeterminate consequences, which will be
important to better define through future research. The
erratic nature of the symptom experience may precipitate uncertainty: while symptom severity and symptom
bother can increase uncertainty (Clayton et al., 2006), the
extent to which symptom-related events are expected, familiar, understandable, and predictable in terms of their
duration and outcome has been shown to decrease uncertainty in other cancers (Clayton et al., 2006).
cation and testing of uncertainty theory in other cancers

has been a similar, restricted focus on symptoms as the
physical effects of the neoplasm and its treatment (Clayton et al., 2006; Mast, 1998; Porter et al., 2006). While
neuropsychiatric symptoms and neurocognitive function
remain additional and essential considerations given the
nature of this patient population, the latter are typically difficult to segregate from outcomes under conditions of uncertainty, and the former fall under a separate
antecedent to uncertainty, that of cognitive capacity
(Clayton et al., 2006; Mishel, 1988; Porter et al., 2006).
Exclusion of these variables limits the findings.
Regardless of treatment status and primary or secondary context, brain tumors often carry an ominous
prognosis, including the potential for significant neurologic and other symptoms, disability, and shortened survival. Presently, there is a continuing need to examine
the symptom experience for brain tumor patients using
population-specific and reliable tools. The symptom findings here indicate a significant risk for uncertainty supporting a targeted evaluation of uncertainty alongside
symptoms as a potential strategy to improve or maintain
QoL for brain tumor patients. There is precedent from
other solid tumors that targeted nurse-led intervention
may impact the experience of symptoms and reduce distress and interference as contributors to uncertainty, improving QoL (McCorkle et al., 2009). These data raise the
possibility that reduction of uncertainty can be mediated
by contextualizing the symptom experience as it occurs
for each individual patient. There is an urgent need to
determine if such strategies can be optimized within the
unique population of brain tumor patients to produce
similar results.
Acknowledgments
This review was supported with a Doctoral Degree
Scholarship in Cancer Nursing from the American Cancer Society.
Clinical Resources
r American Brain Tumor
r
r
Foundation, http://www.
abta.org
National Brain Tumor Society, http://www.
braintumor.org/
National Cancer Institute, http://www.cancer.gov/
Conclusions
This review aimed to describe and evaluate the potential of somatic symptoms as an antecedent to uncertainty
in brain tumor patients. A defining feature of the appliJournal of Nursing Scholarship, 2012; 44:2, 145155.

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CLINICAL SCHOLARSHIP

Brain Tumor Symptoms as Antecedents to Uncertainty:

Despite significant advances in treatment and survival,

can degrade quality of life (QoL; Lovely, 2004; Lovely,

Brain Tumor Symptoms and Uncertainty

distinct from the more prevalent metastatic (secondary)

Symptoms and Uncertainty

Exploring Symptoms as Potential Antecedents

Knafl (2005), the purpose of this integrative review was

Journal of Nursing Scholarship, 2012; 44:2, 145155.

Retrospective chart review Ependymomas in United

Armstrong, Cron, et al.

Armstrong et al. (2009)

Primary tumors in United

Armstrong et al. (2006)

Headache & others

Lung, breast, colorectal,

Prospective, cohort study

Argyriou et al. (2006)

Symptoms & inventory

Malignant primary tumors

Retrospective case review

Arber et al. (2010)

Sample & setting

Purpose & design

Article & discipline

Table 1. Symptom Findings in Primary and Metastatic Brain Tumors

(4%), headaches (4%), extrapyrimadal (3%), seizures (3%),

r 56% had 1 or more symptoms; 10% had 4+

Chow et al. (2005)

Bosma et al. (2009)

Brown et al. (2006)

Purpose & design

Article & discipline

Grade 3 & 4 gliomas in

Brain metastases from

Symptoms & inventory

Primary brain tumors in

Sample & setting

fatigue (44%), numbness or tingling (39%), pain (36%),

r Recurrence: numbness or tingling (25%), headache (25%)

weakness (33%), seizures (12%)

r Treatment-related symptoms (primarily surgery):

Brain Tumor Symptoms and Uncertainty

Journal of Nursing Scholarship, 2012; 44:2, 145155.

Retrospective chart review Primary or metastatic

Gleason et al. (2007)

Journal of Nursing Scholarship, 2012; 44:2, 145155.

Hird et al. (2010)

Lynam et al. (2007)

PostdiagnosisMixed: pre- Multiple FACT

Brain metastases from

Multiple COGMOS; BPI;

Fox et al. (2007)

Symptoms & inventory

Brain metastases from

Chow et al. (2008)

Sample & setting

Purpose & design

Article & discipline

(37% of variance); Cluster 2 = anxiety, depression (12%

r Clusters: Cluster 1 = fatigue, drowsiness, SOB, pain

(88.1%), drowsiness (82.2%) anxiety (82.1%).