Glioblastoma: Introduction

While primary malignant brain tumors account for

only two percent of all adult cancers, these neoplasms
Background, cause a disproportionate amount of cancer-related
disabilities and death. The five-year survival rates for

Standard brain tumors are the third lowest among all types of
cancer. Malignant gliomas (glioblastoma and anaplas-
tic astrocytoma) comprise the most common types of

Treatment primary central nervous system (CNS) tumors and

have a combined incidence of five to eight cases per
100,000 people. The median survival rate of conser-
Paradigms, and vatively treated patients with malignant gliomas is 14
weeks; with surgical resection alone, 20 weeks; with

Supportive Care surgery and radiation, 36 weeks; and with the addi-
tion of newer biochemotherapies such as temozolo-
mide and bevacizumab, upward of 14-18 months.1

Considerations The profound cost of caring for terminally ill

Susan V. Ellor,
Teri Ann Pagano-Young, and
Nicholas G. Avgeropoulos
patients with primary malignant brain tumors raises
ethical considerations for the American public; the
stewardship of health care dollars for the popula-
tion at large maintains a juxtaposed tension against a
dynamic, necessary balance of hope, care, rehabilita-
tion and research efforts for affected patients and their
advocates.

Definition
The World Health Organization (WHO) brain tumor
classification system offers a universally accepted cate-
gorization of intracranial lesions based on histological
characteristics. Brain tumors fall under several broad
categories, namely glial (e.g., astrocytic, oligodendrog-

Susan V. Ellor, Ph.D., M.D., is currently in the intern year

of her Neurology residency at the Duke University Medi-
cal Center. She completed requirements for her Ph.D. in
neurobiology at the University of Florida and attained her
M.D. at the University of Central Florida College of Medi-
cine. Dr. Ellor was selected as one of the few students for the
charter class and awarded with a full scholarship to attend.
Teri Ann Pagano-Young, M.S.N., A.N.P.-B.C., is a Neurol-
ogy/Neuro-Oncology nurse practitioner at UF Health Cancer
Cener at Orlando Health in Orlando, FL. Ms. Pagano gradu-
ated from the University of Florida in 2001, receiving her
Masters of Science in Nursing/Adult Nurse Practitioner cer-
tification and has been working with adult neurology pa-
tients since 2001. She has worked exclusively with brain and
spine tumor patients since 2009. Nicholas G. Avgeropoulos,
M.D., serves as Co-Director of the Brain and Spine Tumor
Program at UF Health Cancer Center at Orlando Health.  He
is the Director of Neuro-Oncology there and is board certi-
fied by the American Board of Psychiatry and Neurology as
well as the United Council for Neurologic Subspecialties.  Dr.
Avgeropoulos’ residency training in Neurology was completed
at the Medical University of South Carolina.  His subsequent
fellowships include Neuroimmunology/Neurovirology, Neu-
ropathology, and Neuro-Oncology.  Dr. Avgeropoulos is active
in national brain and spine tumor research and advocacy
efforts.

neurosciences • summer 2014 171

S Y MPO SIUM

lial, ependymal, and mixed), neuroepithelial, choroid,

syndrome, and there does not seem to be a familial
neuronal and mixed neuro-glial, pineal parenchymal,
predilection otherwise. Interestingly, there is a clear
and those with neuroblastic or glioblastic elements
and inverse association between allergy, asthma, IgE,
(embryonal).  and glioma risk.8
Glioblastoma (GB, formerly glioblastoma multi-
Efforts to identify specific associations with occupa-
forme or GBM) is the highest grade (IV) of astrocytic
tional or environmental exposures have been largely
tumor.  WHO grade IV  astrocytomas are mitotically
underpowered or inconclusive. Ionizing radiation
active, vascular, and necrosis-prone. Their tendency
is one of the few factors that definitively show an
toward rapid, invasive progression requires an aggres-
increased risk of brain tumors, including glioma. Gly-
cidol, a compound used in the manu-
facture of Vinyl polymers, synthetic
hydrolic fluids and epoxy resins, is
The profound cost of caring for terminally ill also suspected to increase susceptibil-
patients with primary malignant brain tumors ity to glioma, although this association
raises ethical considerations for the American has only been strongly demonstrated
in animals to date.9 Although many
public; the stewardship of health care dollars for studies have explored the relationship
the population at large maintains a juxtaposed between cellphone use and glioma
tension against a dynamic, necessary balance of risk, long-term exposure studies are
hope, care, rehabilitation and research efforts for only now becoming achievable due to
their relatively recent use prevalence
affected patients and their advocates. and the ongoing refinement of expo-
sure assessment techniques.10

sive treatment paradigm.2 Lower grade astrocytic
tumors include pilocytic and subependymal giant cell
astrocytomas, pleomorphic xanthoastrocytoma (grade
I), and diffuse astrocytoma (grade II).3  Sellar tumors,
hematopoietic tumors, germ cell tumors, meningeal,
peripheral nerve, and metastatic lesions are also
important causes of neurological morbidity and mor-
tality, albeit outside the scope of this article.   or other focal neurological deficits may be alleviated
Epidemiology
The National Cancer Institute estimates that there
were 22,910 new diagnoses and 13,700 deaths from
primary tumors of the nervous system in the United
States in 2012. GB constitutes 80 percent of intracere-
bral gliomas and 20 percent of all intracranial tumors.
They may also appear in the brainstem, cerebellum, or
spinal cord.4 Both Surveillance Epidemiology and End
Results (SEER) and Central Brain Tumor Registry of
the United States (CBTRUS) estimate GB incidences
to be between two and five out of every 100,000 peo-
ple.5 The mean age of presentation is in the mid-60s,
but this tumor type may occur at any age. The inci-
dence is slightly higher in men (1.6:1) and Caucasians,
relative to other ethnic groups.6
Although the risk of glioma is increased in certain
highly-penetrant genetic diseases, such as neurofibro-
matosis 1 and 2, retinoblastoma, tuberous sclerosis,
Turcot’s syndrome and Li-Fraumeni,7 fewer than one
percent of glioma patients have a known hereditary
Presenting Signs and Symptoms
Patients often present with symptoms of increased
intracranial pressure, including headache and sei-
zure, and may have focal neurologic findings related
to the extent, acceleration of growth and location of
the tumor and associated vasogenic edema. Symp-
toms from mass effect such as headache, somnolence,
by dexamethasone treatment, usually in the range of
4-10mg q6-12h.   Anti-epileptics are not considered
to be necessary for prophylaxis in patients without a
history of seizure, although many neuro-oncologists
prescribe them in anticipation of tumor growth and
dynamically increased risk of cerebral cortical irrita-
tion leading to seizure activity.11
Imaging
The quintessential radiographic presentation of GB
is that of an irregularly shaped heterogeneous mass,
often with a hypointense center representing necro-
sis, a ring of enhancement and surrounding vasogenic
edema causing mass effect. Depending on the size and
location of the lesion, ventricular distortion or displace-
ment may also be appreciable.12 Correlative pathol-
ogy studies have revealed tumor cells to be present in
areas of peritumoral edema and beyond; as such, this
volume is reconciled to best define the parameters of
radiation therapy.13 Diagnosis and response to therapy
can be difficult to assess with standard head comput-

172 journal of law, medicine & ethics


erized tomography (CT) or brain magnetic resource
imaging (MRI) alone, as the extent and distribution of
contrast “enhancement” reflects the extent of blood-
brain barrier compromise more than strictly changes
in tumor size.
“Pseudoprogression” is the term for suspicious T2
(long echo and repetition time settings on MRI) or
post-contrast imaging findings that are caused by
reactive changes in the brain parenchyma and not
principally by tumor growth. These changes may have
resulted from interventions such as surgery, radia-
tion and/or chemotherapy, yielding subsequent radi-
ation necrosis or other iatrogenic impact that may
be misinterpreted as true tumor progression. The
opposite phenomenon may be produced by antian-
giogenic agents or steroids, which are known to alter
neuroradiological disease assessment by tightening
the blood-brain and blood-tumor barriers, yielding
“pseudoregression.”
Considering these limitations to standard imaging,
some clinical researchers remain skeptical regarding
progression-free survival (PFS) as a primary end-
point; instead, referring to a more definitive over-
all survival (OS) as the “gold standard” endpoint for
clinical efficacy.14 Recent updates from the Response
Assessment in Neuro-Oncology (RANO) committee
recommend the use of supplementary technology,
such as magnetic resonance spectroscopy and perfu-
sion, in addition to clinical and steroid utilization data
to better define and homogenize PFS as a more tan-
gible outcome measure.15
Pathology
Grossly, glioblastoma has a variegated appearance,
often mottled in color, reflective of the degree of
necrosis and presence of hemorrhage.16 The tumor is
confirmed by a craniotomy, allowing for maximum,
feasible therapeutic resection. An open or stereotac-
tic biopsy is performed in situations where eloquent
brain is involved and at risk. Microscopic examina-
tion characteristically reveals a densely cellular tumor
with significant pleomorphism and nuclear atypia.
Hyperplasia of small vessel endothelium with vas-
cular thrombosis, necrosis, and/or hemorrhage dis-
tinguishes GB from lower grade astrocytomas.17 The
histologic grade may vary among different areas of
the tumor; therefore, low-grade astrocytoma and glio-
blastoma may coexist along a spectrum. The highest-
grade component determines tumor behavior, which
is why these tumors are given the designation of their
most aggressive cellular constituents.18
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Ellor, Pagano-Young, and Avgeropoulos
Pathophysiology
Most glioblastomas appear as a heterogeneous lesion
in the deep white matter and have a tendency toward
rapid infiltration into surrounding parenchyma.
Approximately 50 percent involve both hemispheres,
and three to six percent are multifocal. Unusually,
these tumors have the potential to produce menin-
geal gliomatosis, form distant foci on spinal roots, or
involve the bone or lymph nodes.19 The typical loca-
tion, mechanism of growth and spread, cellular, and
genetic heterogeneity and behavior of high-grade
gliomas suggest that these tumors arise from neu-
ral or glial progenitor cells that undergo malignant
transformation.20
Prognostic Indicators
Glioblastoma has the highest mortality of primary
brain tumors. Approximately half of the patients are
alive at one year after diagnosis, and less than 10 per-
cent are alive at five years after diagnosis.21 The most
significant, unfavorable prognostic indicators include
when the patient age is over 40 years, higher histo-
logical grade, and lower performance status (Table 1,
Figures 1-3).
Relative youth is a notably favorable prognostic
indicator, with an 18-month median survival of 66
percent for those under 40 years versus less than 10
percent for patients 60 years and older. Whether this
is attributed to tumor or host-dependent factors is not
fully elucidated.22 Also, tumor grade is strongly cor-
related with survival time, with patient survival aver-
aging three to five years after diagnosis of anaplastic
(WHO grade III) astrocytoma.  
The Karnofsky Performance Scale (KPS) index is a
measure of the patient’s performance status at a given
point in time (Table 1). It may be used to assess the
effectiveness of therapy and estimate prognosis. In
general, the higher the score, the better the progno-
sis.23  Typically, the neuro-oncology clinician will make
note of this number at the initial presentation, many
times for clinical trial screening purposes, and use
this scale at subsequent encounters as a rough clinical
endpoint to track how the patient is progressing over
time. 
Other predictors of more negative outcomes include
a tumor size of greater than 5-6 cm, tumors crossing
the midline, contrast enhancement on imaging, and
neurologic deficits. The coexistence of at least three
of these risk factors predicts a significantly short-
ened life expectancy.24 In most cases, death ultimately
results from cerebral edema and elevated intracranial
pressure.
The molecular profile of the glioma also bears an
increasingly recognized and prominent prognostic
S Y MPO SIUM

Table 1
Karnofsky Performance Status Scale Rating (%) Criteria

Able to carry on normal activity and to

  
work; no special care needed
Unable to work; able to live at home and
care for most personal needs; varying
amount of assistance needed
Unable to care for self; requires equiva-
lent of institutional or hospital care;
disease may be progressing rapidly
100   Normal no complaints; no evidence of disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Normal activity with effort; some signs or symptoms of disease
70 Cares for self; unable to carry on normal activity or to do active work
60 Requires occasional assistance but is able to care for most personal needs
50 Requires considerable assistance and frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled; hospital admission is indicated although death not imminent
20 Very sick; hospital admission necessary; active supportive treatment necessary
10 Moribund; fatal processes progressing rapidly
0 Dead

value, with favorable markers including promoter-
methylated MGMT, isocitrate dehydrogenase (IDH) 1
mutation, and 1p/19q co-deletion. This is partially due
to their resistance or regulation of available therapies.
Alkylating chemotherapeutics add alkyl groups to
DNA, which is cytotoxic and induces apoptosis in sus-
ceptible cells.  The O(6)-methylguanine-DNA meth-
yltransferase (MGMT) gene on chromosome 10q26
codes for a DNA repair enzyme that removes these
alkyl groups from the 0-6 position of guanine, coun-
teracting the drug’s mechanism of action.
Fortunately, a subpopulation of malignant gliomas
often have the MGMT gene inactivated due to aberrant
methylation of its promoter region,25 making the tumor
cells more vulnerable to alkylating chemotherapeutics,
such as the first line agent temozolomide. Other mark-
ers of histologic value include 1p/19q codeletion, which
more strongly correlates with oligodendroglioma and
the isocitrate dehydrogenase-1 (IDH-1) mutation that
often accompanies grade II/III gliomas, rather than
primary or secondary GB. Primary glioblastoma mani-
fests de novo, whereas secondary GB arises from trans-
mogrification of lower grade.
P53 tumor suppressor mutation is more often noted
in younger patients with glioblastoma arising from
lower-grade astrocytoma, while epidermal growth
factor receptor (EGFR) tyrosine kinase amplification
is often seen in older patients with primary glioblas-
toma. Although EGFR is often mutated, amplified or
over-expressed in astrocytic tumors in general, this
does not equate to a clinical response to targeted ther-
apies. It is estimated that 10 to 20 percent of unstrati-
fied patients with progressive glioblastoma will have
a radiographic response to EGFR kinase inhibitors.
Ingo Mellinghoff et al. recognizes that the EGFR
mutant variant III (EGFRvIII), when co-expressed
with PTEN tumor suppressor, is associated with a
clinical response of gliomas to EGFR-kinase inhibi-
tors such as erlotinib.26
The EGFR pathway is often abnormally activated
in human cancers, including glioblastoma. While
EGFRvIII expression has been recognized for some
time, there are relatively few datasets that define a
consistent clinical outcome in this population.27 How-
ever, a consistent theme within these publications is
that long-term survival for patients with EGFRvIII
expression is very poor, with very few patients surviv-
ing beyond two years and with prognosis appearing
to be independent of previously identified prognostic
factors.
Standard of Care
Treatment paradigms for glioblastoma are aggressive
and rely on multi-modality strategies, typically involv-
ing maximum feasible surgical resection followed by
chemo-radiation and adjuvant chemotherapy.28 Clini-
cal research studies that have been vetted through the
usual scientific and ethical rigors should be considered
at any step of the treatment decision-making process
to augment or enhance therapeutic outcome for this
tumor because it has no set cure. Surgical resection
confirms histology and often alleviates symptoms

174 journal of law, medicine & ethics

 Ellor, Pagano-Young, and Avgeropoulos

Figure 1
Age

Figure 2
KPS

Figure 3
KPS

neurosciences • summer 2014 175

S Y MPO SIUM
caused by increased intracranial pressure or compres-
sion, therefore decreasing reliance of corticosteroids.
Completeness of resection has been shown to corre-
late with survival rates, particularly in patients with a
good baseline performance status.29
A large retrospective study by R. K. Yabroff et al.
analyzes treatment and response data from 1,202
GB cases nationwide that were diagnosed in 2006,30
one year after our current treatment guidelines were
instated (EORTC protocol). Using SEER data, this
group found that survival varied significantly by sur-
gical intervention, with the shortest survival among
patients not receiving surgery and those receiving
local excision or biopsy only, and the longest survival
among patients receiving partial or total resection.
This prognostic significance is maintained among
those receiving post-surgical TMZ and RT (n=562),
with patients living significantly longer after gross
total resection versus partial resection (median sur-
vival of 20 months versus 13 months, respectively).31
A large prospective study involving 565 patients
with GB also demonstrated a powerful correlation
between aggressive surgical resection and duration
of survival (P<0.0001). 32 However, in contrast to
the focal and well-demarcated brain tumors such as
meningiomas, the infiltrative nature of glioblastoma
makes total resection to the microscopic impossible,
and certain locations within the brain are not safely
operable for resection. In addition, the location of the
lesion could impart an independent risk factor.
The patient should wait two to four weeks after a
standard surgical resection to allow for proper wound
healing prior to starting chemo-radiation. The stan-
dard dosing of fractionated EBRT for treatment of
high-grade gliomas is 60 Gy in 1.8–2.0 Gy fractions
administered weekdays over six weeks (roughly 30
fractions). Concomitant oral temozolomide (TMZ)
capsules are given at 75 mg/m2 daily during this
period.33
Temozolomide chemotherapy is started concomi-
tantly with radiation for several reasons. Not only have
in vitro studies demonstrated mechanistic synergy
between these modalities, but radiotherapy is under-
stood to assist spontaneous conversion of temozolo-
mide into the active metabolite, as well as the drug’s
ability to traverse the blood-brain barrier. Moreover,
daily administrations of concomitant low-dose temo-
zolomide allow for increased dose-intensity by nearly
a factor of two as compared with the standard regi-
men, without an increase in toxicity.34 This concomi-
tant treatment is followed by at least six to 12 months
of adjuvant temozolomide administered on days one
through five of each 28-day cycle.35
176 journal of law, medicine & ethics
Temozolomide (Temodar) is a newer methylat-
ing agent administered orally as a prodrug.36 TMZ
became the standard of care for glioblastoma based
on a landmark study by the European Organisation
for Research and Treatment of Cancer (EORTC) and
the National Cancer Institute of Canada Clinical Tri-
als Group (NCIC).37 This phase III study involves
573 patients from 85 centers and shows that two-
year survival more than double from 10 to 27 percent
among those treated with concomitant and adjuvant
temozolomide plus radiotherapy versus radiotherapy
alone. This is consistent with the group’s prior phase
II trial.38
Although improvement in median survival
increased from 12.1 months to 14.6 months, the study
reports survival benefit in nearly all subgroups defined
according to known prognostic factors. This averaged
figure includes the patients whose age and comorbidi-
ties compromise their prognosis; therefore, it is rea-
sonable to suspect that the benefit to healthy young
patients is understated by these numbers.39
It is also noteworthy that patients in the EORTC/
NCIC study average just three cycles of adjuvant temo-
zolomide therapy (range zero to seven cycles), most
often due to tumor progression prior to or after start-
ing treatment. This falls far short of the six–12 cycle
exposure targeted in clinical practice. In fact, an infor-
mal survey of American neuro-oncologists reveals
that 70 percent target one year of adjunct temozolo-
mide treatment, while an additional 20 percent tar-
get two years of treatment.40 A five-year follow up of
the EORTC/NCIC study reveals higher five-year sur-
vival figures, particularly in MGMT favorable patient
subgroups.41
Though typically well tolerated, myelosuppression is
a major concern of temozolomide use, and irreversible
thrombocytopenia, aplastic anemia, and even death
have resulted from use.42 The EORTC/NCIC study
reports that radiotherapy plus temozolomide results in
grade three or four neutropenia or thrombocytopenia
leading to discontinuation of the drug in eight percent
of patients. Expectedly, such hematologic toxic effects
are not observed in the radiotherapy-only treatment
group.43 The addition of temozolomide during radia-
tion treatment had minimal impact on the frequency
of severe infection (three percent versus two percent
in the radiation-only group), although five percent of
patients on adjuvant temozolomide in the post-radi-
ation phase of treatment acquired severe infections.  
By far, the most common treatment-related com-
plaints among glioblastoma patients are those of
fatigue and constipation. The EORTC/NCIC study
reports moderate to severe fatigue occurring in 26
percent of patients in the radiotherapy group versus

33 percent in the radiotherapy-plus-temozolomide
group.44
Other chemotherapeutic agents considered for
treatment of glioblastoma include procarbazine, car-
boplatin and the nitrosourea compounds carmustine
(BCNU) and lomustine (CCNU). A 2002 meta-analy-
sis of over 3,500 patients reveals that adjuvant chemo-
therapy with these agents increases two-year survival
from nine percent to 13 percent for individuals with
glioblastoma, and 31 percent to 37 percent for those
with anaplastic astrocytoma.45
The combination of procarbazine, CCNU and
vincristine (PCV) is less commonly utilized in the
past 10 years due to increased toxicity and inferior
results relative to TMZ.46 Similarly, a recent study
comparing alternative chemotherapeutic regimens
finds that combination therapy  with 6-thioguanine,
capecitabine, and celecoxib plus CCNU or TMZ does
not appear to be more effective than other alkylating
agent schedules for patients with recurrent glioblas-
toma, despite earlier promising results for recurrent
high-grade anaplastic glioma.47
GLIADEL  Wafer (polifeprosan 20 with carmus-
tine implant) is indicated for use in patients with
newly diagnosed high-grade malignant glioma as an
adjunct to surgery and radiation. It is also indicated
in patients with recurrent glioblastoma as an adjunct
to surgery. Moreover, recent studies demonstrate safe
administration of adjuvant temozolomide in patients
previously implanted with carmustine wafers.48 Prior
to the use of TMZ, both cisplatin and carboplatin were
used as first line agents with demonstrated survival
similar to BCNU. However, significant nephrotoxicity
and ototoxicity associated with cisplatin and myelo-
suppression, albeit to a lesser degree associated with
carboplatin, limits their desirability and risk/benefit
ratio value.49
Patients nearing completion of their prescribed
chemotherapy sometimes wish to continue treat-
ment beyond the preset number of cycles originally
targeted. This desire is often fueled by the fear that
the therapy is all that is maintaining cancer remis-
sion. With respect to TMZ, for example, the literature
is largely devoid of large-scale studies reflecting long-
term (more than one year) exposure, leaving clinicians
with only case reports, personal experience and small
series as their guidepost.50
Nevertheless, the decision of whether or not to
extend therapy beyond current guidelines bears con-
sideration of many factors beyond evidenced-based
practice, including potential toxicity (as described
above), induction of tumor resistance, generation of
secondary malignancies, such as leukemia, and mon-
etary cost.
neurosciences • summer 2014 177
Ellor, Pagano-Young, and Avgeropoulos
On the other side of the argument, tumor recur-
rence increases the possibility of more surgery, radia-
tion therapy, and repeat or alternative chemotherapies
— all with likely physically and financially devastating
sequelae. Thus, continuing the “gold-standard” ther-
apy past its proven period of benefit may be worth the
risk and investment if it bears even a modest chance of
deferring recurrence, particularly in the case of a bet-
ter-tolerated oral agent. In addition, continuing a drug
that is successful based on tolerability profiles, rather
than predetermined protocols, may enhance response
rates (self-fulfilling prophecy consideration). A patient
who fears recurrence but discontinues therapy under
the pressure of his or her physician may place blame
on the physician if or when the cancer returns, despite
aggressive counseling.
With a paucity of scientific data quantifying the
true risks and benefits of protracted treatment, it is
imperative that the treatment decision arises from
a mutually satisfactory discussion of what is and is
not known and what this means to the individual
patient. Such effective, informed consent fulfills an
important duty by honoring the principle of patient
autonomy. Although the issue of physician liability
remains unclear, it is at a minimum essential to have
documentation signed by the patient and a witness
reflecting that “the patient was told the [known] risks
and hazards that could have influenced a reasonable
person in making the decision to give or withhold
treatment.”51
Recurrence is almost inevitable for high-grade
gliomas, and treatment in these patients must follow
consideration of not only tumor location and growth
pattern, but also the patient’s age and overall state of
health. The majority of recurrences arise within two
cm of the original tumor site, and about 10 percent are
accompanied by additional non-contiguous lesions.  
If tumor presentation and patient health permits,
treatment of recurrent disease may include surgery,
another trial of temozolomide, or second-line chemo-
therapy such as carmustine, biological treatment, and
re-irradiation. As with the primary lesion, outcomes
of re-resection are highly influenced by the area and
size of tumor involvement and the patient’s Karnofsky
score.52 A large pooled analysis of European Organiza-
tion for Research and Treatment of Cancer (EORTC)
trials that included 300 patients with recurrent glio-
blastoma concluded that WHO performance status (p
greater than or equal to 0.0001), but not age (p = 0.21),
is a major prognostic factor for PFS and OS in recur-
rent GB.53 Moreover, undergoing surgery for recur-
rence did not significantly impact survival (p=0.25)
but did improve quality of life and functionality. They
find that patients with large and/or multiple lesions
S Y MPO SIUM
have shorter PFS and OS, whereas frontal lesions are
associated with improved survival.54
Anti-angiogenic agents such as bevacizumab (Avas-
tin) may also be considered, particularly in the context
of progression, despite temozolomide monotherapy.
Bevacizumab is an antibody that targets and neu-
tralizes vascular endothelial growth factor (VEGF),
therefore inhibiting the growth of blood vessels and
impeding the growth of certain tumors.55 In addition
to its anti-angiogenic properties, it has also proven
beneficial for reducing vasogenic edema associated
with radiation necrosis.56 Because it can repress vas-
cular leakiness, it can also produce a falsely promising
radiographic improvement known as pseudoregres-
sion,57 independent of the actual tumor response.
Although the phase II study that led to bevacizumab’s
FDA approval for single-agent treatment of recur-
rent GB only demonstrated a two-month increase in
median overall survival, many patients with recur-
rence do experience significant and even striking
improvement in quality of life and neurological func-
tioning after starting bevacizumab.58 Real-world sce-
narios highlight that even when quantity is limited,
quality of life is a stand-alone factor when considering
the value of care.
Cost-Effectiveness of Treatment
The principles of beneficence, justice, and autonomy
are essential to discussions on the cost of cancer care.
Indeed, a plethora of more sophisticated chemothera-
peutics and molecularly targeted agents that are now
available to cancer patients are largely responsible
for the exorbitant cost of modern cancer treatment.59
Because of their widespread use, studies from around
the globe have examined the cost-effectiveness of sev-
eral treatments utilized for GB patients.   third-party insurers do not have this limitation to the
Temozolomide is used in glioma patients as first- or
second-line treatment. Generally, these studies con-
clude that despite the relative expense of the drug,
the incremental cost-effectiveness of temozolomide as
adjuvant treatment is in line with other accepted can-
cer treatments.60 Standard 28-day cycles of temozolo-
mide may cost upward of $3,000–$4,000 per five-day
course.
Bevacizumab at a standard dose of 10 mg/kg every
two weeks runs $5,000 or more per infusion. While
patients with private insurance or governmental ben-
efits may have access to a potentially life-extending
and quality-of-life improving treatment like this,
many Americans are underinsured, if they have health
insurance at all. A patient with even 80 percent of
prescription costs covered is still left to pay $1,000
per month out of pocket, which is likely not feasible,
178 journal of law, medicine & ethics
especially for those who have been disabled and out of
work with such a dismal prognosis.
It appears fair and responsible to discuss treat-
ment options with patients initially outside of consid-
erations of cost, and then to inform the patient that
there are financial parameters that may drive treat-
ment decision making contingent on the strength of
the evidence backing utilization of the agent in ques-
tion. Reconciliation of the financial picture ahead,
including costs associated with medications, copays,
time away from work, transportation, infusion suite
and facility fees, laboratory and imaging costs as well
as other professional fees, along with the other cen-
tral issues such as methods of administration, side-
effects, alternatives and expected outcomes, must
couple with the standard discussion of prescribing
a particular medication. Presenting the facts in this
way respects the principle of autonomy and discloses
the context of the physician’s injection of his or her
personal value scale into what may be the most per-
sonal and significant decisions that patient will ever
make.
To the credit of the health care business, physicians,
health care institutions, and pharmaceutical com-
panies often contribute substantial finances to treat
uninsured and underinsured patients. This has been
an expectation of society that is placed on few other
businesses: services rendered without expectation for
the requested value of remuneration by the consumer.
Perhaps this has been workable to date because the
financial profitability margins for all parties involved
have been substantial enough to allow such benevo-
lence, so long as the cost burden is absorbed and sub-
sidized equitably between providers within discrete
geographical regions/socioeconomic profiles. Because
degree stated above and state and federal health care
resources are becoming relatively scarce, financial
pressures and care for more of the public will almost
certainly come to the point of crisis while various spe-
cial interests dig in their heels to control where resid-
ual money goes.
Quality of Life During and After Therapy
In recent years, there has been increased awareness
with regard to the quality of life of oncology patients.
Quality of life refers to the physical, psychological, and
social domains of health as perceived by the patient
and influenced by the patient’s own unique beliefs and
expectations. As discussed above, instruments such as
the Karnofsky Performance Scale (KPS) can be used
as a global determination of a patient’s quality of life.
These issues are important to the oncologic physician
from an ethical point of view in terms of beneficence
 Ellor, Pagano-Young, and Avgeropoulos

and non-maleficence.  That is to say, the treatment
should provide potential benefit to the patient while
keeping complications and deleterious side effects to
an acceptable minimum.61  pathology, palliative medicine, and other medical pro-
Certain anti-cancer therapies for brain tumors can be
approved on the basis of quantity of life without symp-
toms or toxicity, without having to prove an extension
to the length of life. Most recently, the Novocure device,
an alternating current tumor repressive therapy, was
FDA approved as a single intervention for recurrent/
progressive GB in patients who have exhausted other
treatment options.62 The device itself was approved
in a non-inferiority study compared against standard
chemotherapies with respect to survival outcomes and
yielded better quality of life outcomes against the same
control. The transition from an anti-cancer, interven-
tion-based approach to one of pure palliation (hospice)
multidisciplinary team of a neuro-oncology center is
comprised of specialists from neurology, neurosur-
gery, medical oncology, radiation therapy, radiology,
fessions. The role of nursing, psychology, social work,
physical or occupational therapy, speech therapy, and
neurocognitive rehabilitation are similarly vital to
total care of the brain tumor patient.
Psychosocial Support
GB patients cope with common issues, including
uncertain prognosis, cognitive deficits, disruption in
mood, clinical depression, and loss of familiar identity
and self-image. However, these issues are further com-
plicated by limited insight, social isolation, frustration
directed toward significant others/caregivers, and an
unlikely return to baseline functioning. Moreover,

The participation of a psychologist, neuropsychologist, social workers, and

counselors on a neuro-oncology team is strongly desirable as part of an
integrated approach to provide the best patient care. Neuropsychological
testing for disability assessment and baseline for future cognitive
intervention, personal and financial advice for the patient and caregiver,
managing depression, and instructions on handling emergency situations is
a necessary part of the palliative process. As brain tumor patients experience
the greatest inabilities for depressive coping amongst oncology patients,
psychologists who work with these patients should have oncology experience.

is an individualized and many times represents a con-
tinuum in terms of balancing timing, severity of illness,
response to and tolerance of treatments, and other
emotional and psychosocial factors.
The Interdisciplinary Rehabilitation Team
In 1971, the National Cancer Act was introduced,
which included rehabilitation as an objective. This
led to research and development and in 1972, the
National Cancer Institute introduced four objectives
at the National Cancer Rehabilitation Planning Con-
ference: psychological support, optimization of physi-
cal function, vocational counseling, and optimization
of social functioning. In 1981, the broader categories
of preventative, restorative, supportive, and palliative
measures were refined as goals in the rehabilitation
process.63
As in any other disease process, cancer rehabilita-
tion is best approached as a comprehensive, multi-
disciplinary team process. The interdisciplinary and
with disproportionately limiting neurological disabil-
ity and frequent requirements for chronic adminis-
tration of psychoactive medications, GB patients are
less able to provide self-care. Frequently, substantial
cognitive loss is progressive in nature. As caregivers
grow less tolerant and optimistic about recovery, pro-
fessional support tends to dwindle for many reasons,
which in turn yields a less optimal patient outcome. 64
The participation of a psychologist, neuropsycholo-
gist, social workers, and counselors on a neuro-oncol-
ogy team is strongly desirable as part of an integrated
approach to provide the best patient care. Neuropsy-
chological testing for disability assessment and base-
line for future cognitive intervention, personal and
financial advice for the patient and caregiver, manag-
ing depression, and instructions on handling emer-
gency situations is a necessary part of the palliative
process. As brain tumor patients experience the great-
est inabilities for depressive coping amongst oncology

neurosciences • summer 2014 179

S Y MPO SIUM
patients, psychologists who work with these patients
should have oncology experience.65
Neurocognitive Rehabilitation
Changes in cognition, personality, and general iden-
tity are critically problematic throughout the process
of dealing with GB. There are numerous factors that
contribute to the etiology of cognitive impairment in
patients with a brain tumor, including tumor effects,
treatment effects, medications, super infections,
emotional coping, and relevant past medical history.
Specific neurocognitive and neurological deficits are
related to the location, geometry and acceleration of
tumor growth. For example, important variables such
as verbal memory and language impairments are asso-
ciated with dominant hemisphere tumors, whereas
visual-perceptual impairments are typically associ-
ated with non-dominant tumors. However, neurobe-
havioral slowing and fatigue are pervasive in patients
with brain tumors, regardless of location.66
In 2000, the Brain Tumor Progress Review Group,
co-sponsored by the National Cancer Institute and
the National Institute of Neurological Disorders
and Stroke, issued a specific call to review cognitive
interventions used in other rehabilitation-related dis-
ciplines to determine whether evidence-based inter-
ventions could be successfully used for brain tumor
patients. The results of a randomized, controlled trial
of cognitive rehabilitation that enrolled 140 glioma
patients revealed favorable group effects with the
intervention group, performing significantly better
than the control group on neuropsychological tests
of attention and verbal memory. The intervention
incorporated both cognitive retraining and computer-
assisted strategy training.67
Unfortunately, many published studies carried out
on the prevention or treatment of cognitive deficits in
patients with brain tumors have sometimes unavoid-
able methodological limitations that impact both the
quality of the research and the ability to draw firm
conclusions. These factors include improved results
with repeated testing over time, regression to the
mean, spontaneous recovery, and delayed interven-
tion effects on cognitive test performed.68
Limitations of Current Rehabilitation for
Brain Tumor Patients
GB patients have complex and fluctuating needs for
rehabilitative intervention, including speech, physical
and/or occupational therapy. For admission into inpa-
tient rehabilitation, the patient must demonstrate the
need for more than one modality of treatment, proof
of continued progress, the capability to endure three
or more hours of therapy each day, consistent motiva-
180 journal of law, medicine & ethics
tion, and a manageable discharge plan.69 With limited
prognosis and the inability to accurately prognosti-
cate treatment response and longevity, as well as the
frequent need to continue active anti-cancer thera-
pies during the inpatient rehabilitative process, it is
difficult to accept glioblastoma patients for inpatient
rehabilitation programs. Patients often need to con-
sider rationing their visits or choose which therapy to
pursue, which makes the process of recovery uneven
and less effective. Given the limited and varied popu-
lation of adult brain tumor survivors, it is difficult to
imagine generating studies with sufficient numbers of
patients enrolled to convincingly and objectively drive
a policy that advocates them.70
Conclusion
Glioblastoma is a brain tumor condition marked by
rapid neurological and clinical demise, resulting in
disproportionate disability for those affected. Caring
for this group of patients is complex, intense, multi-
disciplinary in nature, and fraught with the need for
expensive treatments, surveillance imaging, physician
follow-up, and rehabilitative, psychological, and social
support interventions. Few of these patients return
to the workforce for any meaningful timeframe, and
because of the enormity of the financial burden that
patients, their caregivers, and society face, utiliza-
tion reviews become more important to place under
ethical scrutiny. Hopefully, as treatments allow for
longer-term survival, treatment decision making will
become more standardized and uniformly affordable
and available to the population at large.
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