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Seminars in Oncology Nursing, Vol 00, No 00 (), 2018: pp 1 16 1

TAGEDH1END-OF-LIFE CARE FOR

PATIENTS WITH GLIOMATAGEDEN
TAGEDPD1X XNORISSA HONEAD2AGEDENX XT

OBJECTIVE: To describe best practices and guidelines in symptom management

at the end of life for adults with malignant glioma.
DATA SOURCES: Journal articles, evidence-based reviews, textbooks, and clini-
cal guidelines.
CONCLUSION: Symptom management is an essential element of end-of-life care
that aims to preserve dignity and quality of life for patients with glioma and
their family caregivers.
IMPLICATIONS FOR NURSING PRACTICE: Advance care planning using a holistic
approach to the patient's symptoms experience and goals of care are necessary
to develop, implement, and evaluate outcomes of an evidence-based plan of
care tailored for each patient and family.
TAGEDPKEY WORDS: glioma, glioblastoma, end-of-life care, guidelines, symptoms,
symptom management.

H
igh-grade gliomas (HGG) are the most
common primary malignant brain
tumor.1 Despite aggressive treatment
with surgery, chemotherapy, radia-
tion, and biologic therapy, survival remains poor;
while quality-of-life (QOL) issues and symptom
management remain priorities of care. Patients
with a HGG (eg, astrocytoma, glioblastoma, oligo-
dendroglioma) face a rather predictable disease
trajectory of inevitable physical, neurologic, and/
Norissa Honea, PhD, RN, AOCN®, CNRN: Program
manager, Neurosurgery Clinical Research, Barrow
Neurological Institute at Dignity Health St. Joseph’s
Hospital and Medical Center, Phoenix, AZ.
Address correspondence to: Norissa Honea, PhD, RN,
AOCNÒ , CNRN, Program manager, Neurosurgery Clin-
ical Research, Barrow Neurological Institute at Dignity
Health St. Joseph’s Hospital and Medical Center, Clini-
cal Research Department, Basement, Main Bldg.,
350 W. Thomas Rd., Phoenix, AZ 85013. e-mail:
norissa.honea@dignityhealth.org
© 2018 Elsevier Inc. All rights reserved.
0749-2081
https://doi.org/10.1016/j.soncn.2018.10.013
or cognitive/behavioral decline until death. Many
symptoms, although present throughout the dis-
ease trajectory, may become more pronounced at
the end of life (EOL).2 The EOL phase is often
viewed as the time during the last 3 months of life
when symptom recurrence leads to deterioration
or when active treatment is no longer effective.3,4
Tumor progression and subsequent cerebral
edema cause worsening headache, communica-
tion deficits, seizures, cognitive disturbances, dys-
phagia, decreased mobility, incontinence, with
progressive focal neurologic deficits during this
terminal period.5 Throughout the EOL phase for
patients with glioma, most suffer with loss of a
sense of self,6 loss of independence, and high symp-
tom burden.2,5,7 Thus, symptom management is a
chief concern of care at EOL to promote comfort
and a dignified death that may ease the burden of
their family caregivers.8 Figure 1 shows an over-
view of aspects in the EOL phase that encompasses
symptoms, end-of-life decision-making (ELD), fam-
ily caregiver burden, and organization of care.3 All
of these will come to light through the review as
well.
2 N. HONEA
FIGURE 1. Overview of aspects in EOL phase in high-grade glioma.3 (Adapted and reprinted with permission of &
Taphoorn 4(5) 2015; permission conveyed through Copyright Clearance Center, Inc Elsevier.). EOL, end of life.
The primary aim of this review is to summarize
the current knowledge about the symptoms and
symptom management at EOL in patients with
a HGG and other issues impacting such care
(ie, caregiver burden and ELD). Moreover, it will
provide nurses with evidence-based symptom
management interventions and recommended
guidelines for EOL care for these patients and
their family caregivers.
TAGEDH1METHODSTAGEDEN
Search strategy
A selective literature search was performed using
the PubMed database for years 2012 through Octo-
ber 2017 for English language reviews and studies
about symptoms at EOL in malignant glioma,
including family caregiver issues; and for guidelines
for EOL care for this population. Search terms
included glioma, glioblastoma, end of life, palliative
care (PC), symptoms, symptom management, and
guidelines, reviews, and clinical trials (Fig. 2).
Results
The initial search retrieved 1,634 articles. From
these, 101 were selected to review after excluding
articles using filters of human, English language, and
abstracts. All relevant titles and abstracts with avail-
able full texts were reviewed and reference lists of
relevant articles and reviews were screened for
additional studies. Finally, 27 relevant articles were
deemed eligible for this review. Articles were elimi-
nated if not English language; no available abstract;
related to pediatrics or active treatment phase of
disease; or disease population did not include gli-
oma. Among those meeting eligibility were seven
systematic reviews,5,7,9 12 clinical reviews and stud-
ies that examined symptoms experience,3,4,6,13 18
family caregiver perceptions,8,13,19 23 patterns of
EOL care,13,24 29 and guidelines or recommenda-
tions for care at EOL.3,4,11,12 The main characteris-
tics of applicable studies and reviews are described
in Table 1.
Symptom experience at EOL for patients with
glioma
General symptoms noted at EOL in PC include
fatigue, anorexia, delirium, immobility and incon-
tinence, nausea, anxiety, depression, dyspnea,
bodily pain, and fever for patients with various
types of cancer.5,9,30 Yet, the EOL symptom profile
in patients with HGG differs from other types of
cancers because there is less bodily pain, nausea
and vomiting, dyspnea, and anorexia.5 Table 2
shows the symptoms at EOL in HGG.
Throughout their disease trajectory, many
patients with a HGG must deal with sequelae of
tumor invasion and/or side effects of treatment
aimed at controlling the disease. A prominence of
clinical signs and symptoms found at EOL in
patients with a glioma is assumed to be because of
increased intracranial pressure from tumor
 ARTICLE IN PRESS
Articles identified through PubMed database using
key words (n=1,634)
English language articles identified through
PubMed database (n=101)
Titles and abstracts assessed for eligibility (n=29)
Full texts assessed for eligibility (n=24)
Reference lists assessed for eligible articles (n=6)
Included in Review (n=27)
FIGURE 2. A selective literature search was performed using the PubMed database for years 2012 through October 2017.
progression.3 Koekkoek et al14 examined EOL
phase symptoms in a cohort of 178 patients with a
HGG over time using reports from physicians who
were responsible for EOL care. High symptom fre-
quency ( three symptoms) were already present
in just over half of the patients at 3 months before
death and in nearly 65% of patients the week
before death. Thus, the physician reports indi-
cated that symptom burden increases from
3 months before death to 1 week before death.14
Somnolence and decrease in level of conscious-
ness are often gradual, yet are the most commonly
reported symptoms at EOL,3 5,9,13,14,17 with the
incidence increasing during the last 7 to 10 days
before death.14,17 Increasing somnolence limits
communication with the patient and, thus, a reli-
ance on family caregiver as proxy for determining
pain and/or QOL. Such increasing somnolence
also impedes the administration of oral medica-
tions. Sometimes somnolence is preceded by
delirium, often described as agitation, restless-
ness, or confusion. Delirium has been reported to
occur in up to 85% of patients during the dying
phase.4 The cause of delirium may be because of
factors other than the tumor itself, such as medi-
cations (steroids, opioids, benzodiazepines, etc.),
dehydration, or infections.4
END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA 3
Excluded (n=72)
Not high grade glioma related
Not end-of-life related
Not adult population
Excluded (n=3)
Not Review or trial
Cognitive disturbances such as confusion and
agitation diagnosed by neuropsychological assess-
ment have been reported in up to 54% of patients
with a glioma during their disease course.3 How-
ever, reports of cognitive disturbance are between
15% and 51% during the EOL phase.5,9,14 Such
symptoms are a cause of stress for family care-
givers, adding to their burden of caregiving,23,31
and increase as the patient moves closer to death.14
Focal neurologic deficits are also reported as
present in nearly two thirds9 of patients, with
severity often increasing as the tumor progresses.4
Such deficits lead to decreases in functional status
in nearly three quarters of cases, as reported in
the review by Sizoo et al.5 One study on Austrian
caregivers reported that 22% of patients were bed-
bound during the last 3 months of life and in 80%
during the final week.19 Dirven and colleagues3
reported that immobility occurs in 77% of patients
and as a result of (1) hemiparesis because of
tumor, (2) proximal leg weakness because of long-
term steroid use, (3) loss of coordination from sen-
sory issues, or (4) balance issues and falls from
dizziness.3 However, Koekkoek et al14 reported
that the incidence of focal neurologic deficits did
not increase during the last week of life compared
with 3 months before death.
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TABLE 1.

N. HONEA
Articles in Review

Study Region of origin Article type Population Topics covered, specific Results
content
Alturki et al25 Canada Retrospective cohort— Patients with PMBT Processes of care in 90% of patients had at least one admission to an acute
chart reviews (n=1,623) last 6 months and care hospital and 23% spent at least 3 or more of the
predictors for place of last 6 months of EOL in an acute care setting; 44%
death had been to an ER at least once and 30% were
admitted to ICU. Only 18% had a physician home
visit.; 10% died at home, 49% in hospital, and 40%
died in a PC facility. Those receiving higher intensity,
more curative care were more likely to die at places
other than home.

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Collins et al23 Australia Qualitative interviewsCurrent and bereaved Examined supportive Themes: challenge of caring, lack of available support,
family caregivers of and PC needs with and the suffering of caring
adults with PMBT focus on EOL
(n=23)
Diamond et al24 US Retrospective cohort— Patients with PMBT Rates and risks of early 22.5% enrolled in hospice (late) within 7 days of death,
chart reviews (n=160) v late hospice referral often with severe neurologic debilitation; more likely
in urban area to be male, of lower SES and without a health care
proxy.
Dirven et al3 Netherlands Clinical review Patients with anaplastic Different aspects of EOL symptoms in patients with PMBT differ from
astrocyctoma care in EOL phase for patients with other cancers. Care of these patients
patients with glioma; involves symptom management, ELDs, organization
EOL care of care, and caregiver burden. Advanced care
recommendations planning and discussion of patient preferences
should occur before the patient has cognitive decline.
Flechl et al19 Austria Cross-sectional Bereaved family Caregiver’s view of the 29% of caregivers felt completely unprepared in their
survey— caregivers (n=52) patients’ terminal role; 29% suffered from financial difficulties and
questionnaires phase with GBM, associated with burnout and lower QOL, which did
QOL, quality of care, not differ between patients who died in a hospital
and place of death (46%) or those who died at home (40%).
preferences
Heese et al20 Germany, Switzerland Cross-sectional Glioma family 15-item questionnaire Two thirds of patients had at-home care during the last
survey— caregivers (n=605) about medical, 4 weeks of life; 47.7% who died at home, 22.6% died
questionnaires logistic, and mental in hospital, and 19.3% died in a hospice facility.
health support; and Medical support was by general practitioners in most
symptom control cases (72.3%), and by 30% hospice or nursing
during final 4 weeks home-affiliated physicians; general oncologists and/
EOL or NO were involved much less (17%, 6%). Nursing
service support was rated highest ahead of medical

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 TABLE 1.
(Continued)

Study Region of origin
Koekkoek et al14 Netherlands, Belgium, Questionnaires
Austria, Scotland
Article type Population Topics covered, specific Results
content
and mental health support.; 22.9% reported no offer
of mental health support to caregivers.
Physician in charge of Disease-specific Main symptoms of concern: motor deficits, headache,
EOL care for patients symptoms, general cognition, seizures, dysphasia, and somnolence, with
with HGG (n=178); EOL symptoms, the latter two most prevalent during the last week of
family caregiver as symptom frequency, life as in 81% of patients in whom medications were
patient proxy (n=87) and medication use at withdrawn; in 96% of those where AEDs were
3 months and 1 week withdrawn. High symptom frequency negatively

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before death; quality affects perceived quality of care.
of care as perceived
by family caregivers
Koekkoek et al15 Netherlands Feasibility study Patients with glioma Prophylactic use of Results demonstrate feasibility of treating seizures at
with a history of buccal clonazepam at EOL phase with a combination of non-oral
epilepsy nearing EOL onset of dysphagia; benzodiazepines; and seems to allow some level of
and their family intranasal midazolam comfort to caregivers in their ability to manage
caregivers (n=25) for acute seizures seizures at home.
Koekkoek et al4 Netherlands Clinical review Patients with glioma Symptoms, symptom Alternate routes for administration of medications
and their family management; ELD, should be considered when regular oral treatment (ie,
caregivers organization of care, AED) is no longer possible because of dysphasia,
role of informal declining consciousness and/or communication.
caregiver ELDs about advance care planning and treatment
decisions should take place early in the disease

END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA

course so patient preferences can be known.
LoPresti et al10 US Systematic review Family caregivers/ Ethnic minority EOL Health and health care disparities exist for minorities.
(k=25) patients with cancer decision making; Use of hospice by minority groups compared with
family involvement; whites were less than half or equal in Hispanic
provider Americans, lesser than in African Americans, and
communication; least in Asian Americans. Urban locale was
religion and associated with lower hospice use but more referrals
spirituality; patient for Hispanic and Asian Americans. Religious and
preferences cultural beliefs strongly influenced decision making
for African and Hispanic Americans, especially ELD
about preferences for life-prolonging measures and
advance care planning.
Oliver et al11 European Association of Systematic review Patients with Goal: establish Limited evidence exists to support recommendations
Palliative Care Taskforce, (k=942) progressive evidence-based but increasing evidence that PC and a
in collaboration with the neurologic disease consensus for PC and multidisciplinary approach to care leads to improved

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5
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TABLE 1.

N. HONEA
(Continued)

Study Region of origin
Scientific Panel on
Palliative Care in
Neurology of the
European Federation of
Neurological Societies
(now the European
Academy of Neurology)
Article type Population Topics covered, specific Results
content
and their family EOL care for patients symptoms and QOL for patients and families.
caregivers with progressive Consensus found and recommendations made for
neurologic disease early integration of PC, involvement of wider
and their families multidisciplinary team, communication with patients
and families about advance care planning, symptoms
management, EOL care, caregiver support and
training, and education for all professionals involved
in the care of patients with chronic and progressive

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neurologic disease.
Pace et al12 European Association of Systematic review Adults with glioma Symptom Developed guidelines for PC and EOL care for adult
Neuro-Oncology (k=251) management, patients with glioma
nutrition, hydration,
and respiration;
advance care
planning
Pace et al18 Italy Retrospective analysis Adults with HGG at Seizure incidence at Of those (36.9%) presenting with seizures in the last
EOL at home (n=157) EOL month of life, 86.2% had prior seizures and 13.8%
were seizure free.
Philip et al6 Australia Qualitative grounded Adult patients with Explored the supportive Patients suffered pervasive loss of self and had
theory—interviews PMBT (n=10) and PC needs across substantial needs that were not shared or addressed
the disease trajectory by the current medical system of care.
Sizoo et al22 The Netherlands Questionnaires Physicians and family Patients’ ELD More than half of the patients became incompetent to
caregivers of cohort of preferences and make ELD because of delirium, cognitive deficits,
deceased patients competence; ELD by and/or decreased consciousness. For 40% of
with HGG (n=101) patient or relative patients, the physician did not discuss ELD
preferences. At least one ELD was made in 72%,
most to discuss withdrawal of medication; 30% of
patients received palliative sedation, and 7%
received physician-assisted death.
Sizoo et al8 The Netherlands Questionnaires Bereaved family Perceptions of EOL: Most caregivers (75%) reported that the patient had a
caregivers of cohort of symptoms health- dignified death. In these cases, there were fewer
deceased patients related QOL, ELD, communication deficits, had fewer transitions
with HGG (n=81) place and quality of between health care settings in the EOL phase, and
EOL care, and dying more often died at their preferred place of death.
with dignity Caregivers also were more satisfied with physician
care at EOL and adequately explained treatment
options.

(Continued on next page)

 TABLE 1.
(Continued)

Study Region of origin Article type Population Topics covered, specific Results
content
Sizoo et al5 The Netherlands, Austria, Systematic review Patients with HGG and Symptoms at EOL, All studies showed disease-specific symptoms were
Scotland (k=17) their family caregivers QOL, and quality of prominent at EOL. QOL declined as death
dying; caregiver approached. Only 13% to 16% reportedly had a non-
burden; organization peaceful death. Stress increased for caregivers as
and location of PC, the patient declined.
supportive treatment, Organization of PC and place of death differed
and ELD between countries.
PC and treatment at EOL are part of neurologic care.
Sizoo et al13

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The Netherlands, Austria Clinical review Patients with neurologic Symptoms, supportive Supportive care may preserve QOL. ELDs are
disorders, including treatment and PC at common and important to anticipate and discuss
brain tumors EOL, ELD, and early in the disease process.
advanced care
planning
Sizoo et al16 The Netherlands Questionnaires Physicians of cohort of Prevalence of seizures Seizures occurred in 29% of patients during the last
deceased patients and use of AEDs at week of life; 33% of whom had a history of seizures
with HGG (n=92) EOL and 22% did not. Only a history of status epilepticus
was a significant risk factor for seizures in the last
week of life.
Sizoo et al21 The Netherlands Psychometric Family caregivers of Evaluation of HRQOL While received support from social environment and
evaluation of cohort of deceased at EOL dying with dignity were rated as good, overall HRQOL
retrospective proxy- patients with HGG in was rated as poor and worsened as death drew near.
reported EOL (n=83)

END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA

questionnaires
Steigleder et al7 Germany Systematic review Patients with advanced Symptom burden, Patients with highest symptom burden and PC needs
(k=22) brain tumors in a PC caregiver burden, were those with PMBT or head and neck cancer.
setting QOL, and social and Caregiver burden was higher in those were the
medico-social impact primary decision-maker at EOL. Recommendations
include using standardized assessment instruments.
Sundararajan et al26 Australia Retrospective cohort Cohort of deceased Examined association Patients with  one symptom were more than five
study—chart reviews patients with PMBT between symptoms, times likely to receive PC. Those who received PC
cases who survived receipt of supportive were 1.7 times more likely to die outside of a hospital.
for at least 120 days and PC and site of
between their first death
hospitalization and
death (n = 678)
Their et al17 Austria Retrospective chart Most frequent signs and Symptoms include decreased level of consciousness
review symptoms and (95%), fever (88%), dysphagia (65%), seizures

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TABLE 1.

N. HONEA
(Continued)

Study Region of origin Article type Population Topics covered, specific Results
content
Patients with GBM in management of such (65%), and headache (33%). Opioids were used in
the EOL phase in a in the last 10 days 95%; NSAIDs in 77%, AEDs in 75%, and steroids in
hospital setting (n=57) before death 56%.
Walbert28 US Literature review (k=46) Literature Integration of PC, A minority of patients with PMBT have interactions with
hospice care, and PC and usually late in the disease trajectory. Models
EOL care in the US of practice for PC service: solo practice, congress
practice, and integrated care.
Timing of PC involvement. Developed questionnaire for

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future study.
Walbert and Khan9 US Systematic review (k=7) Adult patients with HGG EOL symptoms and Drowsiness and loss of consciousness were the most
at EOL interventions common symptoms at EOL. Poor communication,
focal neuro deficits, seizures, dysphagia, and
headaches were frequent, remaining high at EOL.
Walbert et al27 US Cross-sectional Participants (providers) Practice patterns and 51% were referred to PC when symptoms required
questionnaires at 2012 Society for influences of provider treatment and 18% at EOL. Only 51% felt
Neuro-oncology demographics and comfortable dealing with EOL issues; 32% believed
(SNO) meeting training in providing that patient expectations for ongoing active therapy
(n=239) PC for patients with hindered their ability to make PC referrals. Female
HGG gender, formal training in NO and PC and medical v
surgical NO training were significantly associated
with hospice referral, comfort in dealing with EOL
issues, and ease of access to PC.
Walbert et al29 Asia-Oceana (AO), Europe Cross-sectional Collaboration between Compared integration Significant differences about hospice referral patterns:
(EU) questionnaires SNO, EANO, and of PC, hospice care, US providers indicated the highest percent of
Asian Society for EOL care in Europe referrals to hospice, while AO had the lowest and EU
Neuro-oncology and Asia with US in between. Neurosurgeons in the US felt least
(ASNO) members comfortable dealing with EOL issues compared with
who provided abstract neurologist and oncologist groups. Access to hospice
at the 2012 SNO services was reportedly easiest in the US, compared
meeting (n=552) with EU, and not easy in AO.

Abbreviations: PMBT, primary malignant brain tumor; PC, palliative care; EOL, end of life; SES, socioeconomic status; ELD, end-of-life decision making; GBM, glioblastoma multi-
forme; QOL, quality of life; NO, neuro-oncology; HGG, high-grade glioma; PC, palliative care; AED, antiepileptic drug antiepileptic drug; HRQOL, health-related quality of life;
NSAIDs, nonsteroidal anti-inflammatory drugs.
 ARTICLE IN PRESS
The prevalence of headache at EOL is reported
to be variable, from 2% to 62%,3,9 although the
incidence may somewhat decrease as the patient
approaches death.14 Headache complaints may
decrease as death approaches because of somno-
lence and loss of consciousness and the patient’s
inability to communicate. Steroids are frequently
used to alleviate the symptoms of increased intra-
cranial pressure, edema, and headache through-
out the disease course but increasingly during the
last months to weeks of life.9, 13 A number of opi-
oid and non-opioid treatments are used as well to
alleviate headache pain.
Swallowing difficulties are also prominent in the
EOL phase5,9 and increase within the last week
before death,14 making oral hydration, nutrition,
and medication administration difficult and the
risk of aspiration greater. Thus, withdrawal of
some medications and/or alternate routes of medi-
cation administration need to be considered to
effectively manage symptoms.
Seizures are a symptom that cause distress in
family caregivers as many feel unprepared to man-
age at home. Seizure prevalence during the last
weeks of life is common with gliomas, occurring in
36% to 56% of patients,3,5,9,12,16 usually with an
increase in frequency during the last month of
life.12 For example, an Italian study team18
reported on 157 patients who died at home and
found 36.9% of their patients presented with one
or more seizures during the last month before
death.18 Most reported seizures were focal (79%),
with generalized seizures and status epilepticus
occurring less often.18 Approximately one third of
TABLE 2.
Symptoms at End of Life in Patients with High-grade
Glioma
Fatigue
Somnolence, delirium, impaired consciousness
Decreased cognition
Poor communication
Focal motor deficits
Seizures
Headache
Confusion and delirium
Dysphagia
Immobility and incontinence
Fever
Data from Dirven et al,3 Koekkoek et al,4 Sizoo et al,5 Stei-
gleder et al,7 Walbert et al,9 LoPresti et al, Sizoo et al,13
Koekkoek et al,14 Koekkoek et al,15 and Sizoo et al.16
END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA 9
the patients had seizures at onset of disease, yet
late-onset seizures occurred during the last month
of life in three quarters of the cases; with another
11% having had no prior seizures who still exhib-
ited seizures in the last month.18 In a Dutch
study,16 physicians who had been in charge of
EOL care for a cohort of 155 patients with glioma
completed questionnaires about the incidence
and treatment of seizures they oversaw in the last
3 months and at the last week before death. These
physicians reported on 92 of the 155 patients. Of
these cases, 29% had reported seizures occurring
during the last week of life. One third of those
patients had a history of seizures in the past, while
22% did not; and 75% were treated with an antiepi-
leptic drug (AED) before the last week of life. Over
a third of the patients were tapered off AEDs with
seizures recurring; and in the 43% of the patients
who had continued AEDs, breakthrough seizures
still presented.16 The Dutch researchers also
reported that status epilepticus had occurred in
two thirds of the patients in their cohort at the
EOL,16 while Pace et al12 reported SE occurred in
2.5%. The review by Dirven et al3 agrees that the
type of seizures reported most commonly in the
final month before death were focal in nature.3
Koekkoek’s team examined the feasibility of using
buccal clonazepam for prophylaxis of seizures and
intranasal midazolam for acute seizures in the
EOL phase with patients who were no longer
able to take oral AEDs.15 They concluded that the
use of a combination of non-oral benzodiazepines
in EOL phase of patients with glioma seemed to
afford some comfort among family caregivers, who
were better able to manage seizures at home.15
Caregiver perceptions during EOL
Caregiver feelings of being unprepared for their
tasks and having financial difficulties are associ-
ated with caregiver burnout and reduced QOL.19
One’s personal network of emotional and social
support often withdraws from the caregiver as a
patient nears EOL. Many caregivers do not feel
comfortable making requests from within their
personal network for fear of imposing on others’
time.32 The type of support provided at EOL and
by whom (provider) are important to caregivers.
For example, a German study of caregiver percep-
tions of medical, nursing, and psychological sup-
port at EOL found caregivers ranked support of
nursing service as higher than medical support,
and both of these higher than mental health sup-
port, with over one in five caregivers being offered
 ARTICLE IN PRESS
10 N. HONEA
no mental health support.20 Because family care-
givers are often quite overwhelmed with their
caregiving responsibilities, they may not even
know what type of support to consider or request.
Nursing service is usually the most frequent and
consistent providers of EOL care at home or hos-
pice. Nurses assess, teach, and coach family care-
givers about symptoms and symptom management
for their loved one. Thus, nurses are also in an ideal
position to assess, intervene, make recommenda-
tions or referrals, and advocate for mental health
support for such caregivers.
In Australia, Collins et al23 interviewed 23 cur-
rent and bereaved caregivers of adults with a HGG
to understand what the caregivers needed in the
way of supportive and PC. Caregivers described
major needs in three themes: (1) challenges, (2)
lack of available support, and (3) suffering of care-
giving. For example, they described the enormity of
the caregiver role that required them to have con-
tinual availability to address myriad patient needs
(activities of daily living, instrumental activities of
daily living, driving, attending appointments, advo-
cacy, etc.). Frustration and difficulty managing neu-
rocognitive problems were significant challenges.23
This is not unlike reports from other researchers,
who report increased caregiver distress when caring
for someone with neurocognitive and neuropsychi-
atric issues.31,33,34 Lack of care coordination, sup-
port, and a clearly identified contact were issues, as
well as feeling a lack of preparation and resources to
support them in their caregiving role, were cited as
reported by others.19,23 One last theme was identi-
fied, ‘suffering of caring.’23 Caregivers described
their role difficulties as ‘relentless,’ leaving them
with a sense of helplessness. They also struggled
with trying to prioritize others’ needs above their
own and reported a sense of isolation and loneliness
because their usual support network was not avail-
able.23 Most family caregivers suffer with sadness
during EOL period for their loved one, as well as
fear, burnout, job restrictions, and financial difficul-
ties because of juggling their caregiving responsibili-
ties.19,35 Halkett et al have reported that distress
and psychological morbidity do not decrease over
time in cancer caregiving populations.36 Table 3
shows caregiver symptoms and concerns.
Hope for a loved one with a HGG to die with dig-
nity is a desired goal of family caregivers. How-
ever, how one defines ‘dying with dignity’ is not so
simple. One must consider the concept of dying
with dignity or a ‘good’ death, and the values and
meanings that an individual applies to that
TABLE 3.
Caregiver Symptoms and Concerns
Anxiety
Sadness/depression
Frustration
Irritation
Fear
Unprepared in role as caregiver
Exhaustion
Lack of support
Isolation and loneliness
Competing priorities
Job restrictions
Financial difficulties
Data from Dirven et al,3 Flechl et al,19 Collins et al,23 Halkett
et al,36 Petruzzi et al.35
concept. Stewart and colleagues37 proposed a
framework of QOL of dying patients and their fam-
ilies within the context of health care. The frame-
work included patient factors (ie, patient and
family situation, social support for each) affecting
health care, structure (ie, access to, organization
of care, formal support services, and physical envi-
ronment) and process (technical process, decision
making, information, counseling, and interper-
sonal communications), as well as care outcomes
(satisfaction with care, QOL, and length of life).
Communication is crucial. Consider the commu-
nication between a patient and his or her provider,
and honoring the patient’s wishes about the man-
ner and place in which they want to die (at home,
hospital, or hospice). In one study, Dutch
researchers sought caregiver perceptions about
their own satisfaction with physicians, the ability
of patient to communicate, and not having to
move between care settings, finding these as most
predictive of a dignified death.8
Health-related quality of life (HRQOL) is a mul-
tidimensional construct that includes physical,
cognitive, emotional, spiritual, social functioning,
and overall QOL.21,38 Caregivers as proxies for
patients with a glioma at EOL responded to ques-
tionnaires about HRQOL in the study by Sizoo
et al.21 Those caregivers corroborated claims that
in patients with glioma at EOL, symptom burden
increases as death approaches and therefore rated
overall QOL as poor.2,5,20
Patterns of EOL care for patients with glioma
Provider practice patterns for the integration of
PC in neuro-oncology vary by patient preference,
 ARTICLE IN PRESS
country, and region within a country, specialty
training, and gender.27 29 A brief historical review
leads to a broader understanding of how practice
has changed through the years.
The movement for PC was first recognized in
the United Kingdom in 1967, originally with atten-
tion to EOL care needs of patients; and the first
hospice unit in North America was established in
Canada nearly 10 years later in 1976. However, it
was not until 2007 that PC was recognized as a
specialty in the United States by the American
Board of Medical Specialties. In the US there has
been a rather clear separation between PC and
hospice because of Medicare reimbursement
guidelines and a fixed rate of reimbursement.28
For example, PC medicine is offered concurrently
with active treatment of disease, while hospice
services are offered only when life expectancy is
less than 6 months and the patient no longer
receives active treatment to control disease.
This also impairs a provider’s referral to hospice
when a patient and/or their family prefer to con-
tinue active treatment. This may be because of
the emphasis on cure above care in the health
care model of medicine.
Walbert28 described three different conceptual
models of PC delivery that are seen in the US.
One is the solo oncologist practice model, where
the provider manages all care, even at EOL; while
the Congress practice model is when the oncolo-
gist will refer to an expert subspecialist in PC. In
this model, the patient sees providers indepen-
dently at different visits and requires a high level
of coordination and communication collaboration.
The third model is that of the integrated care
model, where the patient sees oncologists and
TABLE 4.
Models of Palliative Care Delivery in the United States
Model Features
Solo oncologist Manages all care for the
practice patient through treatment
and at EOL
Congress Primary oncologist makes
practice model referrals to expert PC
specialist
Integrated care Integrated team of oncologists
model and PC specialists in a
comprehensive setting
Abbreviations: EOL, end of life; PC, palliative care.
Data from Walbert.28
END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA 11
subspecialists in a comprehensive setting without
extra visits28 (see Table 4). In a study conducted
through the collaboration of the Society for
Neuro-oncology (SNO), the European Association
of Neuro-oncology (EANO), and the Asian Society
for Neuro-oncology (ASNO), providers responded
to questionnaires about their practice and gave
insight into the comparisons across international
practice patterns in neuro-oncology with regard to
PC and EOL care. With regard to EOL care for
neuro-oncology patients, there were significant
differences found in referral patterns to hospice,
as reportedly, there were more referrals to hospice
by the US providers compared with the Asian-
Oceanic (AO) providers who made fewer referrals
and the European (EU) providers reported a per-
centage between those of the US and AO.29 The
researchers also reported that the providers from
AO felt less comfortable in dealing with EOL issues
than those from the US. With regard to the US pro-
viders, it was reported that while neurologists and
oncologists felt more comfortable with EOL issues,
neurosurgeons did not. Access to hospice care was
also queried of the providers surveyed. Providers
from AO disagreed that their patients had easy
access to hospice, while the US providers reported
that their patients did have easy access and the
EU providers either agreed or were neutral about
ease of access to hospice for their patients.29
The organization of care is important when it
comes to place of death and varies across coun-
tries. For example, patients with a HGG who died
at home occurred in 66% of cases in the Nether-
lands, 66% in Italy, and 40% in Austria, whereas
patients in Anglo Saxon regions more often chose
hospice units (up to 68%) over death at home
Advantages/disadvantages
Advantage: continuity of care, established rapport, and/or trust
with provider
Advantage: has experts involved to manage complex care
Disadvantage: patient sees each provider independently at
different visits. Requires collaboration and high degree of
coordination and communication between providers.
Advantage: coordinated care delivered without additional visits
and may reduce costs. Many of the complex issues are
addressed.
 ARTICLE IN PRESS
12 N. HONEA
(34%).3 Patterns and place of death were specifi-
cally studied by teams in Canada25 and Aus-
tralia.26 A Canadian research team25 found that
90% of the primary brain tumor cases they
reviewed had at least one acute hospitalization
and nearly a quarter had spent 3 or more months
of their last 6 months of life in acute care. They
also reported that 44% had at least one emergency
room visit, with 30% of those resulting in ICU
admissions. The majority had no home visits by a
physician. Nearly half of the patients died in a hos-
pital, 40% in PC facility, and only 10% died at
home. If a patient was thought to succumb quickly
to their disease, no PC referrals were made and
patients with a brain tumor had fewer interactions
with a PC specialist than those with other types of
cancer. Care burden was related to a higher
chance of dying in a hospital, while having a glio-
blastoma had the opposite effect.25 While the rela-
tionship of age of patient to the place of death
were contradictory in some reports, Alturki et al25
hypothesized that age was likely a proxy variable
for social support and/or health-care network. In
comparison, a study from Australia reported that
25% of the patients with malignant glioma died in
hospital, 26% outside of hospital, and about half in
a PC/hospice setting.26 Those with higher symp-
tom burden were more likely to receive PC and
those who did receive PC were 1.7 times more
likely to die outside of the hospital. This statement
points to the value of earlier intervention by PC
service. Another study, described earlier, exam-
ined HRQOL in the Netherlands and found that
the place of death did not affect the perceived
overall QOL or dying with dignity.21
Diamond and colleagues24 examined rates and
risk for late referrals to hospice in patients with
primary malignant brain tumors, claiming late
referrals to hospice as common in the US, with
22.5% enrolled within 7 days of death. Patients
who were bedbound, aphasic, unresponsive or
dyspneic, male, with lower socioeconomic status,
and those without a health care proxy were more
likely to receive a hospice referral within the last
7 days of life.24 Providers may delay referrals to
hospice for EOL care based on the patient’s or
family’s desire to continue active treatment.
Sabo and Johnston stated that, “In the acute
care system, cure continues to be regarded as an
indicator of success. A good HCP will strive to
achieve that goal regardless of the consequen-
ces.”39,p.50 As disease progresses, aphasia, cogni-
tive decline, and psychological impairments can
hinder communication and compromise a
patient’s informed decision-making capacity.39
Waiting to make ELDs places a greater burden on
family caregivers as they struggle to do what they
believe is preferred or best for their loved one.
Another group surveyed providers on their
practice patterns about the use of PC and hospice
in neuro-oncology.27 Differences in the use of PC
and hospice were based on provider level, their
medical specialty, gender, and training in PC. For
example, those with more formal neuro-oncology
or PC training during residency, fellowship, or
those having more than 6 months training via
educational courses were more comfortable with
ELDs and much more likely to refer their patients
to hospice for EOL care. Providers seeing more
than 15 brain tumor patients per week were also
more likely to refer to hospice for EOL care.
Advanced practice providers (mostly female in
the study), disagreed with physicians who
reported ease of access to hospice (48% dis-
agreed, 74% agreed, respectively). Female physi-
cians responded that they referred patients to PC
more than male physicians, and referred the
majority of their patients to hospice for EOL care
74% of the time compared with 44% of time by
their male counterparts. Those in neurology or
medical oncology were much more comfortable
addressing ELD than were neurosurgeons. This
may be because of the amount of time a provider
spends with a patient over the course of the dis-
ease trajectory. The only difference noted
between practice settings was less agreement
about the use of PC specialists being involved in
care at the time of diagnosis of patients with high-
grade gliomas at academic compared with non-
academic settings.27
Disparities within health care are also known
to occur for minorities at EOL. LoPresti and col-
leagues10 examined EOL care for people with
various types of cancers among various ethnic
groups in the US. Racial and ethnic cultural, reli-
gious beliefs, and spiritual coping influence EOL
discussions and decisions (ELD) about preferen-
ces and options for EOL care; for example, Afri-
can American and Hispanic patients who held a
philosophical view of fatalism or who spoke of
“God’s will” in the progression of disease or at
EOL.10 Hispanic patients/families were 2.5 times
more likely to decline hospice services if they
had family available to provide care. Research-
ers reported that African Americans were less
likely to hold a do not resuscitate (DNR) order
 ARTICLE IN PRESS
END-OF-LIFE CARE FOR PATIENTS WITH GLIOMA 13

than other groups, preferring more life-prolong- TAGEDH1RECOMMENDATIONS AND GUIDELINESTAGEDEN

ing measures; and hospice service was least uti-
lized by Asian Americans. Provider factors also
add to disparity, as was reported that providers
adhered to the EOL preferences of non-minority
patients more often than African American.10
ELDs may include issues such as palliative seda-
tion and/or perhaps physician-assisted suicide
with a goal of hastening death. Physician-
assisted suicide is legally allowed in Netherlands,
Luxembourg, Germany, Switzerland, Japan,
Albania, Finland, and Canada, as well as a few
US states (Oregon, Washington, and Ver-
mont).3,4 As mentioned earlier, cognitive decline
can also impact ELDs and therefore occur less
often with patients who have a HGG. Sizoo et
al22 claimed that because of patient’s early cog-
nitive decline, providers did not conversations
about ELDs with the patient; however, there
were discussions with the family caregiver, usu-
ally to discuss withdrawal of steroid.
The following is a synthesis of the information
forming the best level of evidence for symptom
management for patients at EOL and also for
assisting patients and family caregivers in address-
ing EOL issues. Discussions should not wait until
EOL is imminent. They should occur early enough
in the disease course to include the patient to hear
his or her preferences about EOL and to be able to
respect their wishes. Each of the topics that follow
should be included as part of ELD in preparing for
EOL care. Table 5 highlights recommendations
and guidelines for EOL care in patients with HGG.
Table 6 highlights interventions for assisting fam-
ily caregivers at EOL.
Corticosteroids (dexamethasone) are a staple
medication in neuro-oncology to manage symp-
toms of increased intracranial pressure related to
tumor and/or treatment effect. They are often
effective in controlling headache but must be

TABLE 5.
Guidelines for Symptom Management at EOL

Headache Corticosteroids (dexamethasone), opioids, NSAIDs

Delirium Treat underlying cause
Seizures AEDs for as long as possible. Use alternate route if able.
Benzodiazepines: buccal clonazepam for prophylaxis and intranasal midazolam or rectal diazepam for
acute seizures
Nutrition and hydration Consensus on futility of these interventions
Delirium Benzodiazepines; if ineffective, then palliative sedation with barbiturates, ketamine, or propofol
Respiration If uncomfortable, change posture/position; glycopyrronium to reduce sound of respirations, although
no evidence (Cochrane) of effectiveness of pharmaceutical interventions for noisy respirations
Incontinence Urinary catheter for comfort

Abbreviations: AEDs, antiepileptic drugs; EOL, end of life; NSAIDs, nonsteroidal anti-inflammatory drugs.
Data From Pace et al,12 and Koekkoek et al.14

TABLE 6.
Guidelines for Assisting Caregivers at EOL

Caregiver burden Assess regularly using the Distress Thermometer

Preparedness for role
Advance care planning
discussions
Identify a range of support services with referrals if requested
Encourage to see primary care provider for checkup
Psychoeducational interventions
Cognitive behavioral therapy
Information, information, information
Demonstration/re-demonstration
Use PAUSE and REMAP acronyms to guide discussions with patient and family. Include patient
choice as much as possible Be respective and cognizant of cultural and religious beliefs and
values, incorporating into plan of care
 ARTICLE IN PRESS
14 N. HONEA
weighed against the side effect of delirium. At
EOL, steroids may be withdrawn if the patient has
increasing somnolence and is no longer swallow-
ing. Withdrawal of steroids from a patient who is
unconscious has not been associated with an
increase in severity of symptoms.4,14
Opioids and non-opioids are often effective in
relieving pain. Bodily pain has been found to be
less often reported in patients with HGG. The
type, dose, and frequency of pain medications
used depend on the cause and severity of pain.3,4
Dyspnea may also be treated with opioids, most
commonly morphine, and can be given by various
routes (eg, oral, rectal, intramuscular, etc.).
Benzodiazepines are useful in treating anxiety,
seizures, agitation, or delirium, and can be given
orally, rectally, buccal, or subcutaneous. When
used to control seizures, buccal clonazepam has
been as effective for seizure prophylaxis as subcu-
taneous midazolam, phenobarbital, and levetira-
cetam when the patient at EOL can no longer
swallow. Rectal diazepam and intranasal midazo-
lam have shown similar effect in treating acute
seizures. The preferred route of administration
will, of course, depend on the place of care. For
example, in a hospital, more drugs may be admin-
istered by intravenous or enteral tube route.
Supplemental nutrition and hydration are often
regarded by patients and/or their family as
enhancing comfort and QOL. With regard to delir-
ium thought to be related to dehydration, in one
study there was no difference in delirium scores
and survival found between those who did and did
not receive parenteral hydration at EOL.40
Palliative sedation is not given with the inten-
tion to hasten death. Continuous sedation is only
used if the patient has refractory symptoms and a
prognosis of less than 2 weeks. Agents such as
barbiturates, ketamine, and propofol are used if
or when benzodiazepines are not working to alle-
viate symptoms.4
Walbert and Chasteen 41 propose conversations
using the acronym “PAUSE” to guide clinicians as
they assess if the patient is ready to discuss
advance care planning. The first step is to ‘Pause’
during the visit, taking a moment to prepare to
introduce the conversation. Then ‘Ask’ permission
to raise the issue. Help the patient to “Under-
stand” the big-picture values of having an exe-
cuted advance directive. Suggest the patient think
of and choose a ‘Surrogate’ decision maker in the
event he or she is too ill to make decisions. Finally,
‘Expect Emotion’ and acknowledge the difficulty of
the conversation. This is a technique to be used
early on in the disease trajectory. However, when
addressing goals of care for patients in later stage
of disease course, and frequently with a surrogate
decision maker assigned by the patient, the acro-
nym, “REMAP” is useful. ‘Reframe’ why the cur-
rent treatment plan is not working. Expect
‘Emotion’ and empathize. ‘Map’ goals, beliefs, and
values. ‘Align’ with the patient’s values, and ‘Plan
treatment and care that match the patient’s val-
ues. There will probably be questions from the
patient and/or family. Talk to them about available
support services before bringing up the topic of
hospice. Once advance directives have been exe-
cuted, request that copies be given to all of the
patient’s providers so all know the plan and can
respect the patient’s wishes.
Grief and bereavement for family caregivers
begin while the patient is still alive, often at the
onset of disease and diagnosis. Communication
with family caregivers is essential to help ease
their distress and burden, which is considerably
higher for those with brain tumor patients than
others in the general PC population.5 Assessment
of caregiver needs should occur on a regular
basis. Those in oncology nursing are in a key role
to make such assessments, which can be easily
done by using the Distress Thermometer (NCCN
guidelines for patients: Distress version 1.2017;
https://www.nccn.org/patients/guidelines/can
cers.aspx). When addressing and offering EOL
care, it is most helpful to identify a range of sup-
port services. Psychoeducational and cognitive
behavioral therapy interventions may help care-
givers reduce their burden and perhaps increase
their feelings of role mastery and enhance their
perceptions of their QOL.
TAGEDH1CONCLUSIONTAGEDEN
The importance of allowing patients with a gli-
oma and their family caregivers to participate in
discussions and decisions about EOL care cannot
be over emphasized. Waiting to address patient
preferences about EOL care and advanced care
planning can be disruptive when transition of care
is made late, disrupting continuity of care, com-
munication, and relationships with trusted pro-
viders. Such transitions may be difficult for both
the patient and family. The need for care coordi-
nation cannot be understated.23 Early referrals to
PC and hospice can facilitate adequate symptom
 ARTICLE IN PRESS
management so the patient is comfortable, has a
smooth transition of care and, finally, a peaceful
and dignified death. In doing so, it can also serve
to ease some of the burden that family caregivers
experience in the EOL phase and assist them with
information and supportive resources.
This review has outlined the current state of
knowledge on the major symptoms in patients
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