Clinical Review & Education

JAMA | Review

Glioblastoma and Other Primary Brain Malignancies in Adults

A Review
Lauren R. Schaff, MD; Ingo K. Mellinghoff, MD

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IMPORTANCE Malignant primary brain tumors cause more than 15 000 deaths per year in
the United States. The annual incidence of primary malignant brain tumors is approximately 7
per 100 000 individuals and increases with age. Five-year survival is approximately 36%.

OBSERVATIONS Approximately 49% of malignant brain tumors are glioblastomas, and 30%
are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary
central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%)
and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%),
seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits
(10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast
agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor
biopsy with consideration of histopathological and molecular characteristics. Treatment
varies by tumor type and often includes a combination of surgery, chemotherapy, and
radiation. For patients with glioblastoma, the combination of temozolomide with
radiotherapy improved survival when compared with radiotherapy alone (2-year survival,
27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7];
P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, Author Affiliations: Department of
probable 20-year overall survival following radiotherapy without vs with the combination of Neurology, Memorial Sloan Kettering
Cancer Center, New York, New York
procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI,
(Schaff, Mellinghoff); Department of
0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 Neurology, Weill Cornell Medicine,
patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma New York, New York (Schaff,
includes high-dose methotrexate-containing regimens, followed by consolidation therapy Mellinghoff); Human Oncology and
Pathogenesis Program, Memorial
with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative Sloan Kettering Cancer Center,
chemotherapy regimens, or whole brain radiation. New York, New York (Mellinghoff);
Department of Pharmacology,
CONCLUSIONS AND RELEVANCE The incidence of primary malignant brain tumors is Weill Cornell Medicine, New York,
approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain New York (Mellinghoff).
tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for Corresponding Author: Ingo K.
glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent Mellinghoff, MD, Memorial Sloan
Kettering Cancer Center,
temozolomide.
1275 York Ave, New York, NY 10065
(mellingi@mskcc.org).
JAMA. 2023;329(7):574-587. doi:10.1001/jama.2023.0023 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

A
pproximately 85 000 individuals in the United States are
diagnosed with a primary brain tumor each year, of which
approximately 29% are malignant.1
Approximately 80% to 85% of malignant brain tumors in
adults are gliomas, which diffusely infiltrate the brain parenchyma.
The fifth edition of the World Health Organization’s (WHO) clas-
sification of Tumors of the Central Nervous System (CNS), which
provides the international standard for the classification of brain
and spinal cord tumors, refers to this group of tumors as adult-
type diffuse gliomas.2 The incidence of glioblastoma, the most
common malignant primary brain tumor in adults, increases after
the age of 40 and peaks in adults aged 75 to 84 years.1,3 Lower-
grade diffuse gliomas usually affect patients younger than 50 years
of age and are further subclassified into astrocytomas and
oligodendrogliomas.4,5
Less common malignant brain tumors in adults include pri-
mary central nervous system lymphoma (PCNSL) and malignant
forms of meningiomas, ependymomas, and other rare brain tumor
types.1 PCNSL is a rare variant of non-Hodgkin lymphoma that pre-
sents in the brain, eyes, or leptomeningeal space without evidence
of extracranial disease. The incidence of PCNSL is approximately 0.5
per 100 000 individuals, and the incidence is increasing in pa-
tients older than 60 years.6,7 Approximately 5% of meningiomas,
the most common primary CNS tumor in adults, are WHO grade 2
(atypical), and 1% to 2% are WHO grade 3 (malignant/anaplastic).1,8
Ependymomas are rare CNS tumors that arise in the supratentorial
brain, posterior fossa, and spine. The incidence is approximately 0.2
to 0.4 per 100 000 individuals, and as a proportion of all primary
brain cancers, they are more common in children. Ependymomas
are classified according to a combination of histopathological and

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 Glioblastoma and Other Primary Brain Malignancies in Adults
molecular features as well as anatomic site and range in growth speed
from benign to malignant.1,9
This review summarizes current evidence regarding diagnosis
and treatment of primary malignant brain tumors in adults.
Methods
Two literature searches of PubMed, restricted to English-language
articles published within the last 10 years, were performed on June
11, 2022, and updated on December 10, 2022, using the following
MeSH terms: glioma, glioblastoma, malignant meningioma, and
primary CNS lymphoma. Articles with the MeSH term pediatric were
excluded. The search, which retrieved 3592 articles, was limited to
clinical trials, meta-analyses, and systematic reviews. This review in-
cludes 110 articles of which 48 were clinical trials and 19 were meta-
analyses or reviews. The remaining 43 articles were identified by the
authors based on their knowledge of literature before 2012 and from
review of citations in retrieved articles: 14 retrospective studies, 11
guideline or consensus papers, 8 original research studies, 4 epide-
miologic studies, 3 case-control studies, 2 prospective cohort stud-
ies, and 1 editorial.
Discussion and Observations
Epidemiology
Less than 5% of adults with a malignant brain tumor report a family
history of brain tumors or have a cancer predisposition syndrome.10,11
However, the contribution of heritability to brain tumor formation
is likely higher, based on germline sequencing12 and analysis using
GCTA (Genome-wide Complex Trait Analysis).13 Prior exposure to ion-
izing radiation to the CNS, usually during treatment for another can-
cer such as childhood leukemia, is a risk factor for brain tumors
(Box).14 Exposure to low-frequency electromagnetic fields is not an
established risk factor.15 There is not high-quality evidence demon-
strating an association between cellular telephone use and brain tu-
mor formation.11,16 An update to the UK Million Women Study, a pro-
spective study of 776 156 women, reported adjusted relative risks
(RR) for ever vs never cellular telephone use of 0.97 (95% CI, 0.90-
1.04) for all brain tumors; there was no increased risk for glioma, me-
ningioma, pituitary tumors, or acoustic neuroma.17 In an interna-
tional case-control study of 4533 glioma patients and 4171 controls,
a history of respiratory allergies (meta-analysis odds ratio [OR], 0.72
[95% CI, 0.58-0.90]), asthma (meta-analysis OR, 0.77 [95% CI, 0.64-
0.93]), or eczema (meta-analysis OR, 0.71 [95% CI, 0.56-0.89]) was
associated with a statistically significant lower risk of glioma.18 Those
with glioma (229 patients) are also less likely than controls (289 pa-
tients) to report a history of varicella virus (adjusted OR, 0.59 [95%
CI, 0.40-0.86]) and have lower levels of immunoglobulin G to vari-
cella virus.19 Immunodeficiency, including HIV/AIDS, is a risk factor
for the development of PCNSL.20
Clinical Presentation
Headache occurs in nearly 50% of patients with a newly diag-
nosed brain tumor.21 Patients with rapidly growing tumors may
develop increased intracranial pressure and present with nausea,
vomiting, or fatigue. Physical examination may reveal papill-
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Box. Commonly Asked Questions
When Should a Headache Prompt Evaluation for Brain Tumor?
Headaches with the following associated symptoms are
concerning for the possibility of a brain tumor and warrant prompt
evaluation. These symptoms include acute, severe headaches that
represent a change from prior headache pattern, new headaches
in older adults or children, headaches that are positional or
worsen with exertion, and headaches associated with any new
neurologic symptoms.
What Causes Brain Tumors?
Exposure to ionizing radiation, such as from prior treatment
for another cancer, is the only known environmental risk
factor for brain tumor development. Immunodeficiency is a risk
factor for the development of primary central nervous system
lymphoma. There is no clear link between brain tumor develop-
ment and power lines, electronic devices, or cellular telephone
use. Most brain tumors are not hereditary.
What Is the Prognosis of a Malignant Primary Brain Tumor?
Most malignant brain tumors are not curable, and the goal of
treatment is disease control and symptom management.
Prognosis varies based on histology, grade, and molecular markers.
Glioblastoma has the worst prognosis with overall survival of
approximately 15 months. Lower-grade gliomas, particularly
oligodendrogliomas with 1p/19q codeletion, may be controlled
for decades.
edema. Transient increases in intracranial pressure can cause epi-
sodic loss of consciousness (plateau waves) and may be mistaken
for seizures.
Patients may develop focal neurologic deficits related to the lo-
cation of the tumor (Figure 1). For example, tumors affecting the fron-
tal lobes (24%)1,22 may cause lack of initiative and difficulties with
processing information and responding appropriately to the envi-
ronment. Tumors in the dominant hemisphere may present with
speech difficulty while nondominant tumors may have more subtle
symptoms of spatial distortion and constructional apraxia. Anosog-
nosia, defined as inability to recognize one’s deficits, may contrib-
ute to delayed symptom reporting. Cranial neuropathies due to lep-
tomeningeal dissemination of disease or increased intracranial
pressure can present with ocular palsies, hearing loss, or dyspha-
gia. Symptoms may arise over weeks to months. As many as 74%
of patients with lower-grade gliomas present with seizures,23 but
tumors can be present for years before symptoms occur or can be
discovered incidentally. PCNSL preferentially affects deep matter
structures, and many patients (≈40%) exhibit behavioral or cogni-
tive changes. Patients with PCNSL who have involvement of the vit-
reoretinal space (≈25%) may present with blurred vision or float-
ers. Slit lamp examination should be performed in all patients with
suspected PCNSL and vitreoretinal biopsy may be diagnostic.7
Diagnosis
Contrast-enhanced magnetic resonance imaging (MRI) of the brain
is the imaging modality of choice when a brain tumor is suspected,
ideally using a standardized brain tumor imaging protocol. 24
Glioblastomas typically show contrast-enhancement on T1-weighted
sequences. T2-weighted/fluid-attenuated inversion recovery
(T2/FLAIR) reveals hyperintense cerebral edema. Central necrosis
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 Clinical Review & Education Review Glioblastoma and Other Primary Brain Malignancies in Adults

Figure 1. Symptoms of Malignant Brain Tumors Related to the Location of the Tumor

Patients with primary brain malignancies may experience

generalized symptoms such as fatigue, seizures, and signs CORPUS CALL
and symptoms related to increased intracranial pressure, OS Corpus callosum
U
such as headache, nausea, vomiting, or papilledema. M
• Cognitive decline • Inattention
Focal neurologic deficits related to the location • Personality change • Fatigue
of the tumor may also develop. This figure lists
some of the most common focal deficits.
Thalamus
Sella Thalamus • Contralateral sensory deficits
• Bitemporal hemianopia • Aphasia
• Headaches
• Symptoms of hormonal deficiencies, such as
Sella
unexplained weight loss or gain, alopecia,
menstrual change, and sexual dysfunction Parietal lobe
• Contralateral sensory deficits
• Contralateral homonymous
inferior quadrantanopia
PA R I E TA L
Frontal lobe LOBE Dominant hemisphere
• Contralateral motor deficits 10% of tumors • Left-right confusion
• Personality change F R O N TA L • Acalculia
LOBE • Agraphia
• Decline in cognition and
executive functioning 25% of tumors • Alexia
Dominant hemisphere O C C I P I TA L Nondominant hemisphere
• Expressive aphasia LOBE • Poor spatial reasoning
3% of tumors • Contralateral neglect
TEMPORAL • Constructional apraxia
Temporal lobe LOBE • Anosognosia
18% of tumors
• Disturbance of auditory
perception
• Memory impairment Occipital lobe
• Seizures CEREBELLUM • Contralateral homonymous
• Contralateral homonymous 5% of tumors hemianopia
superior quadrantanopia
B
R

Brainstem
4%

Dominant hemisphere
AI

Cerebellum
NS
of

• Receptive aphasia • Diplopia • Abnormal gait

tum
TE

Nondominant hemisphere • Facial droop • Nausea • Ipsilateral ataxia • Nystagmus • Vomiting

ors
M

• Decreased musical abilities • Dysphagia • Vomiting • Incoordination • Nausea • Dizziness

and tonal perception • Limb weakness • Headache

Highlighted in this image are signs and symptoms that are related to the location of the tumor. Percent values1 were not available for some parts of the brain and
therefore do not sum to 100.

and signs of local mass effect may also be present. Lower-grade
gliomas are often hypointense on T1-weighted imaging and
hyperintense on T2/FLAIR. PCNSL may be multifocal and demon-
strate homogeneous enhancement and diffusion restriction on
diffusion-weighted imaging. Meningiomas typically demonstrate
homogeneous contrast enhancement and adjacent dural thicken-
ing (Figure 2).
Tumor tissue is required to establish the diagnosis. Patients with
imaging findings suggestive of a brain malignancy should be re-
ferred to a center with advanced neurosurgical techniques.25
Procedures are typically performed under general anesthesia, and
patients are observed in the hospital for several days to monitor for
surgery-related complications. Preservation of neurologic func-
tion, also referred to as maximal safe surgical resection, is a priority,
and patients may undergo awake craniotomies during which repeti-
tive neurologic assessments guide the resection. When tumor re-
section is not feasible, a tumor biopsy should be performed.
Accurate grading of CNS tumors is important for estimating pa-
tient prognosis and requires integration of histological features and
molecular abnormalities2 (Figure 3). For instance, astrocytomas with
mutations in the genes isocitrate dehydrogenase (IDH) 1 (Genbank
accession O75874) or IDH 2 (Genbank accession P48735) and ho-
mozygous loss of the genes cyclin-dependent kinase inhibitor 2A
(Genbank accession P42771) and B (Genbank accession P42772)
(CDKN2A/B) are considered grade 4 even if they lack histological fea-
tures of a grade 4 tumor.2 Molecular testing is also required to di-
agnose glioma subtypes that are characterized by specific molecu-
lar alterations, such as diffuse midline glioma H3 K27-altered or
diffuse hemispheric glioma H3 G34-mutant. Molecular testing can
also help select the most appropriate treatment. For example, O6-
methylguanine-DNA-methyltransferase (MGMT) (Genbank acces-
sion P16455) promoter methylation is characteristic of glioblasto-
mas that are more likely to respond to alkylating agents such as
temozolomide.26 Many centers are using comprehensive DNA se-
quencing and methylation profiling to classify brain tumors.27,28 Re-
ferral to a cancer center should be considered for detailed molecu-
lar analysis and treatment planning.
Patients with CNS lymphoma require a systemic work-up to
differentiate PCNSL from secondary CNS involvement. Patients
with ependymomas require craniospinal MRI and cerebrospinal

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 Glioblastoma and Other Primary Brain Malignancies in Adults
Figure 2. Imaging Features of Malignant Brain Tumors
Glioblastoma Low-grade diffuse glioma
T1 PRECONTRAST
T1 POSTCONTRAST
T2-WEIGHTED FLAIR
Representative brain magnetic resonance images are from patients with
glioblastoma, isocitrate dehydrogenase IDH-mutant low-grade glioma, primary
central nervous system (CNS) lymphoma, and malignant meningioma. Images
include T1-weighted pregandolinium and postgadolinium and
T2-weighted/fluid-attenuated inversion recovery (FLAIR). Magenta arrow
indicates mass effect (left lateral ventricle obscured). Blue arrow indicates ring
fluid cytology following surgery to assess for leptomeningeal
dissemination.
Treatment of Symptoms and Complications
Seizures occur in as many as 75% of patients with glioma.29 Older
antiepileptic drugs, such as phenobarbital, carbamazepine, or phe-
nytoin stimulate the synthesis of hepatic cytochrome P450 en-
zymes and can affect the metabolism of concomitant drugs. Non-
enzyme–inducing antiepileptic agents, such as levetiracetam,
lacosamide, or clobazam are preferred due to fewer drug-drug in-
teractions and improved adverse effect profiles.30 Tumor-directed
treatments may reduce the risk of seizure recurrence.31 For pa-
tients who never had a seizure, routine anticonvulsant prophylaxis
is not recommended.30 The use of antiepileptic drugs periopera-
tively is common, but evidence for this practice is scant.30
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Primary CNS lymphoma Malignant meningioma
enhancement reflective of central necrosis often seen in glioblastoma. Black
arrow indicates homogeneous enhancement characteristic of CNS lymphoma.
Yellow arrow indicates the dural attachment (dural tail) common with
meningiomas. Glioblastoma and malignant meningioma panels show vasogenic
edema on T2/FLAIR sequence, indicated by white arrows.
Cerebral edema is treated with corticosteroids.32 Dexametha-
sone is preferred due to its low mineralocorticoid activity and long
half-life. For severe neurologic symptoms, such as gait impairment
or altered consciousness, a bolus of dexamethasone 10 mg may be
administered followed by 16 mg per day. Mild to moderate symp-
toms, such as headache or sensory deficits, can be managed with
dexamethasone 4 to 8 mg per day without a loading dose. Once- or
twice-a-day dosing is typically sufficient.33 The lowest dose re-
quired for symptom control should be administered,32 and taper-
ing off corticosteroids should be attempted as soon as appropri-
ate. A slow taper (eg, dose reduction every 3-4 days) is
recommended to identify the minimal steroid dose required to con-
trol neurologic symptoms and to reduce the risk of adrenal insuffi-
ciency. Patients receiving the equivalent of prednisone 20 mg daily
for more than a month (ie, approximately dexamethasone 3 mg daily)
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 Clinical Review & Education Review Glioblastoma and Other Primary Brain Malignancies in Adults

Figure 3. Integration of Histological Features and Molecular Alterations in the Revised WHO Classification of Tumors of the Central Nervous System

Adult-type diffuse gliomasa

IDH-wild type IDH1- or IDH2-mutantb

1p/19q Intact 1p/19q Codeletion

Glioblastomac Astrocytoma, NECd Astrocytoma Oligodendroglioma

Astrocytic histology Astrocytic histology Astrocytic histology Oligodendroglial histology
• Oval-to-elongated nucleus • Oval-to-elongated nucleus • Oval-to-elongated nucleus • Round nucleus
• Eosinphilic cytoplasm • Eosinphilic cytoplasm • Eosinphilic cytoplasm • Perinuclear halos
• Branching capillary pattern

Histopathological and molecular characteristics are used to generate an integrated diagnosis and assess WHO tumor grade

WHO Grade 4 WHO Grade 2 WHO Grade 2 WHO Grade 2

• High cellular density
• Marked nuclear atypia
• High mitotic activity
• Necrosis and/or microvascular
proliferation
Or at least 1 of the following:
• EGFR amplification
• TERT promoter mutation
• Concurrent gain of chromosome 7
and loss of chromosome 10
(+7/−10)
• Low or no mitotic activity
• Absence of necrosis and
microvascular proliferation
WHO Grade 3
• Increased cellular density
• Nuclear atypia
• Increased mitotic activity
• Necrosis and microvascular
proliferation absent
• Low or no mitotic activity
• Absence of necrosis and
microvascular proliferation
• CDKN2A and CDKN2B intact
WHO Grade 3
• Increased cellular density
• Nuclear atypia
• Increased mitotic activity
• Absence of necrosis and
microvascular proliferation
• CDKN2A and CDKN2B intact
• Low or no mitotic activity
• Necrosis and microvascular
proliferation absent
WHO Grade 3
• Increased cellular density
• Nuclear atypia
• Increased mitotic activity
• Necrosis and/or microvascular
proliferation

WHO Grade 4
• High cellular density
The WHO Classification of Tumours of the Central Nervous System was revised • Marked nuclear atypia
in 2021 (WHO CNS5). Tumors are graded on the basis of histological features • High mitotic activity
and molecular abnormalities. Tumor grade is intended to reflect the expected • Necrosis and/or microvascular
natural history, with grade 4 tumors having the worst prognosis. Adult-type proliferation
diffuse gliomas, described here, range from grades 2 to 4. Or
• Homozygous deletion of CDKN2A
and/or CDKN2B

a c
Shown are examples for the adult-type diffuse gliomas. This figure does not
include pediatric-type diffuse high-grade gliomas, which can present in adults.
b
Immunohistochemistry with a highly sensitive and specific monoclonal
antibody that recognizes the isocitrate dehydrogenase (IDH)1-R132H-mutant
d
protein is widely used. The IDH1-R132H mutation accounts for approximately
90% of all IDH1 and IDH2 mutations in supratentorial adult-type diffuse
glioma. Testing for non–IDH1-R132H mutations uses DNA sequence
analysis and is necessary when immunohistochemistry for IDH1-R132H
is negative.
IDH-wild-type glioblastomas lack mutations in IDH1 and IDH2. Absence of
immunoreactivity for IDH1 R132H is sufficient to diagnose IDH-wild-type
glioblastoma in patients aged 55 years and older with histologically
classic glioblastoma.
The “not elsewhere classifiable” (NEC) designation indicates that appropriate
diagnostic testing has been performed, and results do not allow for an alternative
diagnosis per World Health Organization (WHO) criteria. Further molecular
work-up should exclude the presence of genetic findings that are associated with
pediatric-type diffuse gliomas and circumscribed astrocytic gliomas.

should receive prophylaxis for Pneumocystis jirovecii pneumonia
(PCP)34 (Table 1). Trimethoprim/sulfamethoxazole prophylaxis re-
duces incidence of PCP in non-HIV immunocompromised individu-
als from 6.2% to 0.2% (RR, 0.15 [95% CI, 0.04-0.62]).34 Gastroin-
testinal prophylaxis with a proton pump inhibitor is recommended
for patients receiving dexamethasone in doses greater than 8 mg
per day in perioperative settings; it is also recommended for pa-
tients treated with anticoagulation, nonsteroidal inflammatory drugs,
or a history of peptic ulcer disease. Myopathy is a common compli-
cation of corticosteroid use in patients with brain tumors. Patients
with steroid-induced myopathy may report difficulty when rising
from a seated position and climbing stairs. Symptoms may resolve
after steroid discontinuation. Bevacizumab, a monoclonal anti-
body against vascular endothelial growth factor A (VEGF-A), can im-
prove cerebral edema in patients with brain tumors who did not re-
spond to steroids or who are intolerant to steroids.32,35,
Venous thromboembolism (VTE) occurs in as many as 30% of
patients with glioma and CNS lymphoma,36,37 often shortly follow-
ing diagnostic surgery.38 Hospitalized neurosurgical patients should
receive prophylactic low-molecular-weight heparin (LMWH) or un-
fractionated heparin, ideally beginning 24 hours after surgery.39
There are no data to support maintenance of VTE prophylaxis after
hospital discharge,40 and there are also only few prospective data
to guide the treatment of VTE in patients with brain tumors. The risk
of intracranial bleeding may increase with the use of anticoagu-
lants, but these data are not definitive,40,41 and anticoagulation is
generally recommended given the significant mortality associated
with untreated VTE. Many neuro-oncologists favor LMWH over

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 Glioblastoma and Other Primary Brain Malignancies in Adults Review Clinical Review & Education

Table 1. Management of Medical Complications of Glioblastoma and Other Primary Malignant Brain Tumors in Adults

Medication Form Dose Mechanism of action Adverse effectsa Comments

Treatment of cerebral
edema
Dexamethasone Oral tablet, Severe symptoms, bolus Long-acting Hyperglycemia, For maintence, the lowest
solution, or 10 mg, then 16 mg/d in corticosteroid, psychiatric/behavioral dose possible for shortest
intravenous divided doses decreases inflammatory disturbance, fluid amount of time should be
Mild-moderate symptoms, mediators, reverses retention, weight gain, prescribed
4-8 mg/d vascular permeability gastritis, myopathy, Add PCP prophylaxis (see
increased infection risk section below) if
Adverse effects are dose continuing ≥3 mg
dependent and increase with dexamethasone for
prolonged exposure ≥1 mo
Bevacizumab Intravenous 10 mg/kg every 2 wk Vascular endothelial Hypertension (19%-42%), May be used for treatment
growth factor hemorrhage (0.4%-7%), of recurrent glioma or
inhibition proteinuria (5%-20%), management of edema
arterial thromboembolism Hold ≥4 wk before and
(5%), deep venous after any surgical
thrombosis (6%-9%), procedures
posterior reversible
encephalopathy syndrome
(0.5%)
Prophylaxis against
PCP (for patients
receiving
dexamethasone ≥3
mg/d for ≥1 mo)
Sulfamethoxazole- Oral tablet Double-strength Interference with Rash, urticaria, Not to be used in patients
trimethoprim trimethoprim 160 mg, bacterial folic acid nausea/vomiting, with sulfa allergy
(preferred) sulfamethoxazole synthesis hepatotoxicity,
800 mg 3×/ wk or thrombocytopenia,
Single-strength hyponatremia
trimethoprim 80 mg, Frequency of occurrence was
sulfamethoxazole not reported
40 mg once/d
Dapsone Oral tablet 50 mg twice/d or Para-aminobenzoic Methemoglobinemia, Check for glucose-6-
100 mg once/d acid antagonist hemolytic anemia, phosphate dehydrogenase
hepatotoxicity, deficiency
dermatologic toxicity prior to
Frequency of occurrence prescribing
was not reported
Atovaquone Oral suspension 1500 mg once/d Inhibits mitochondrial Rash (6.3%-39%), None
electron transport diarrhea (3.2%-42%),
nausea (4.1%-26%),
headache (16%-28%),
erythema multiforme (<1%),
transaminitis (4%-8%)
Pentamidine Inhaled or Inhaled, 300 mg Inhibits topoisomerase Decreased appetite (50%), None
intravenous once/mo or enzymes, interferes leukopenia (10.4%),
Intravenous, 4 mg/kg with functions of nephrotoxicity (45%),
(max 300 mg) once/mo DNA/RNA, bronchospasm (15%),
phospholipids, and cough (38%-62.7%),
protein synthesis fatigue (65.7%)
Treatment of venous
thromboembolism
Enoxaparin Subcutaneous 1 mg/kg every 12 h or Binds and potentiates Hemorrhage (4%-13%), In patients with kidney
1.5 mg/kg once/d antithrombin hepatotoxicity (5.9%-6.1%), injury, antifactor Xa levels
anemia (<16%), may be used to monitor
thrombocytopenia (<3%) effects
Dose adjustment required
for patients with creatinine
clearance <30 mL/min
Edoxaban Oral tablet Following 5 d Factor Xa inhibitor Major hemorrhage Dose adjustment required
unfractionated heparin (1.4%-6.1%), for patients with creatinine
or low-molecular-weight hepatotoxicity clearance ≤50 mL/min
heparin: (4.8%-7.8%)
>60 kg: 60 mg once/d
≤60 kg: 30 mg once/d
Rivaroxaban Oral tablet, 15 mg twice/d for 21 d, Factor Xa inhibitor Hemorrhage Dose adjustment required
suspension then 20 mg once/d (13.4%-36.2%), for patients with creatinine
gastroenteritis (12.5%), clearance ≤50 mL/min
angioedema (<1%)
Apixaban Oral tablet 10 mg twice/d for 7 d, Factor Xa inhibitor Major bleeding None
then 5 mg twice/d (0.1%-2.13%),
hepatotoxicity (<1%)
Abbreviation: PCP, Pneumocystis jirovecii pneumonia. meant to represent the most frequent or most serious adverse effects. Lists
a
Adverse effects were obtained from the IBM Micromedex database and are are not all-inclusive.

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 Clinical Review & Education Review
vitamin K antagonists, mostly based on extrapolation of findings from
studies with few patients with brain tumors.42 Direct oral antico-
agulants have been shown to be noninferior to LMWH in a general
cancer population43,44 and may also be appropriate for patients with
brain tumors with VTE.45-47 In a single-institution retrospective co-
hort study of patients with glioblastoma and VTE treated with either
direct oral anticoaculants or LMWH (n = 121), rates of clinically sig-
nificant intracerebral hemorrhage at 30 days and 6 months fa-
vored the direct oral anticoagulants group (30 days, 0% vs 9%,
P = .11; 6 months, 0% vs 24%, P = .01).45 Systemic anticoagulation
for VTE should be continued for at least 3 to 6 months, but in pa-
tients with brain malignancies, it may be appropriate to continue an-
ticoagulation indefinitely. Placement of an inferior venous cava fil-
ter can be considered when systemic anticoagulation is considered
unsafe, but inferior vena cava filters are associated with a 30% rate
of recurrent VTE.48
Patients with malignant brain tumors experience neurocogni-
tive decline, decreased mobility, fatigue, depression, seizures, and
reduced sexual wellness. Symptom management is an important part
of treatment, and early referral to palliative medicine should be
considered.49 Patients should receive fertility counseling prior to
treatment including information about egg or sperm preservation.
Treatment of Glioblastoma
Glioblastoma is the most common malignant primary brain tumor,
and it has a median survival of less than 2 years (Box). 50,51
Glioblastomas are more common among non-Hispanic White indi-
viduals than other race and ethnic groups, and there is a slight male
predominance.1 Patient participation in clinical trials should be con-
sidered whenever possible, given the limited number of effective
standard therapies for glioblastoma.
Surgical removal of all contrast-enhancing tumor, also referred
to as gross total resection, is associated with improved progression-
free survival and overall survival.52,53 Use of 5-aminolevulinic acid,
an optical imaging agent, aids in the visualization of malignant tis-
sue during surgery and improved rates of gross total resection and
6-month progression-free survival.54 Within 3 to 6 weeks after sur-
gery, patients should receive radiation (60 Gy, typically given over
6 weeks in 30 fractions of 2 Gy) with concurrent administration of
the oral alkylating agent temozolomide. Temozolomide should be
resumed 4 weeks after completion of radiation, typically for 5 con-
secutive days every 28 days for a total of 6 monthly cycles.50,55 In a
clinical trial of 573 participants, this regimen improved survival com-
pared with radiation alone (14.6 months vs 12.1 months; hazard ra-
tio [HR], 0.63 [95% CI, 0.52-0.75]; P < .001).50 Patients with epi-
genetic silencing of the DNA-repair protein MGMT in tumor tissue
(92 patients) benefited the most from temozolomide, with a me-
dian overall survival of 21.7 months (95% CI, 17.4-30.4) compared
with 15.3 months (95% CI, 13.0-20.9) with radiation alone (P = .01).56
Health-related quality of life was similar in patients treated with ra-
diation alone compared with radiation plus temozolomide.57 An-
other clinical trial randomized 562 patients aged 65 years and older
to either short-course radiotherapy alone (40 Gy in 15 fractions) or
radiotherapy followed by temozolomide and demonstrated im-
proved overall survival with combination therapy (9.3 months vs 7.6
months; HR, 0.67 [95% CI, 0.56-0.80]; P < .001).58 In patients un-
likely to tolerate the combination of chemotherapy and radiation,
treatment with either radiation alone (if MGMT unmethylated) or te-
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Glioblastoma and Other Primary Brain Malignancies in Adults
mozolomide alone (if MGMT methylated) should be considered59,60
(Table 2). The combination of maintenance temozolomide and tu-
mor-treating fields, alternating low-intensity electric fields deliv-
ered via transducer arrays on the shaved scalp and connected to a
portable device, improved overall survival in a clinical trial of 695 par-
ticipants from 16.0 months to 20.9 months (HR, 0.63 [95% CI, 0.53-
0.76]; P < .001).51
Glioblastoma recurrence is inevitable, with a median progres-
sion-free survival of approximately 7 months.50,51 Many patients un-
dergo a second tumor resection and additional chemotherapy with
nitrosoureas or temozolomide. Bevacizumab is widely used in the
US to control symptoms from vasogenic edema.3 A recent random-
ized trial (182 participants) reported improvement in 6-month
progression-free survival with re-irradiation in combination with
bevacizumab compared with bevacizumab alone (54.3% vs 29.1%;
P = .01), but there was no difference in overall survival (10.1 months
vs 9.7 months; HR, 0.98 [80% CI, 0.79-1.23]; 1-sided P = .46).71
Many new drugs have not proven effective in late-stage clini-
cal trials, highlighting gaps in early clinical drug development.72
Unlike other intracranial tumors, which respond to small molecule
inhibitors of oncogenic signaling pathways (eg, everolimus,73
selumetinib, 74 vemurafenib, 75,76 ibrutinib, 77 or belzutifan 78 ),
glioblastomas have been largely unresponsive to molecularly tar-
geted therapy. Antibodies targeting the immune checkpoint inhibi-
tor programmed death-1, such as pembrolizumab or nivolumab, also
did not improve overall survival in phase 3 trials79,80 despite alter-
ing the tumor microenvironment.81,82 Current efforts aim to gen-
erate antitumor immunity through intratumoral injection of geneti-
cally engineered herpes simplex virus type 1,83 adenovirus,84 or
poliovirus.85
Treatment of IDH-Mutant Astrocytoma
and Oligodendroglioma
IDH-mutant gliomas comprise approximately 70% to 80% of his-
tologically low-grade gliomas; they commonly occur in patients
younger than 50 years and generally respond better to treatment
than IDH-wild-type gliomas.4,5,86 Oligodendrogliomas are defined
as gliomas with a mutation in IDH and an unbalanced translocation
between chromosomes 1 and 19 (1p/19q-codel); they are graded on
a scale of 2 to 3 based on histological features such as mitotic activ-
ity and presence of microvascular proliferation or necrosis. IDH-
mutant gliomas without 1p/19q codeletion (1p/19q-non-codel) are
astrocytomas and graded on a scale of 2 to 4 based on a combina-
tion of histological features and molecular markers (Figure 3).
Maximal safe surgical resection represents a critical first step in
the treatment of IDH-mutant glioma, with more extensive resec-
tions being associated with improved overall survival.87 A watch and
wait approach with regular MRI surveillance may be appropriate for
younger patients with a WHO grade 2 IDH-mutant glioma, minimal
residual disease, and no neurologic symptoms related to the tu-
mor, with the goal to delay treatment-associated adverse effects (eg,
fatigue, short-term memory loss). Post hoc analysis of the coopera-
tive group NRG Oncology/Radiation Therapy Oncology Group
(RTOG) 980267 showed that patients with high-risk IDH-mutant
WHO grade 2 glioma (ie, patients aged 40 years and older or with
subtotal resections) benefited from the addition of procarbazine,
lomustine, and vincristine to radiotherapy (IDH-mutant 1p/19q codel
[37 patients]; overall survival, 13.9 years [radiotherapy] vs not
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 Table 2. First-Line Treatment of Adult-Type Diffuse Glioma

Dose and frequency of administration

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Treatment options Radiotherapy Chemotherapy Efficacy Adverse effectsa
Glioblastoma, IDH-wild type, grade 4b
Radiotherapy and 60 Gy in 30 Concurrent temozolomide 75 mg/m2 orally once/d during Median overall survival, 14.6 mo for patients treated with Grade 3/4 toxicities: hematologic (16%)50
temozolomide followed fractions radiotherapy radiotherapy and temozolomide vs 12.1 mo for radiotherapy
50
by temozolomide with or Adjuvant temozolomide 150-200 mg/m2 orally once/d on d alone (HR, 0.63 [95% CI, 0.52-0.75]; P < .001)
without tumor-treating 1-5 of six 28-d cycles Addition of tumor-treating fields associated with median
fields overall survival of 20.9 mo vs 16.0 mo without (HR, 0.63
Tumor-treating fields >18 h/d for 2 y or until second
progression [95% CI, 0.53-0.76]; P < .001)51
Glioblastoma, IDH-wild type in patients not appropriate for above regimen (elderly, frail, or poor KPS), grade 4b
Short-course 40 Gy in 15 Concurrent temozolomide 75 mg/m2 orally once/d during In patients ≥65 y considered not suitable for full-dose Grade 3/4 toxicities: anemia (3/270), leukopenia
radiotherapy with or fractions radiotherapy radiotherapy, addition of temozolomide to 40 Gy (19/270), lymphopenia (73/270), neutropenia (22/266),
without temozolomide Adjuvant temozolomide 150-200 mg/m2 orally once/d on d radiotherapy improved median overall survival from 7.6 to thrombocytopenia (30/270)58
followed by 1-5 of each 28-d cycle, ≤12 cycles 9.3 mo (HR, 0.67 [95% CI, 0.56-0.80]; P < .001)58
temozolomide
Short-course 40 Gy in 15 In patients ≥70 y with KPS≥70, radiotherapy improved No grade ≥3 acute toxicities62
Glioblastoma and Other Primary Brain Malignancies in Adults

radiotherapy alone fractions or median overall survival from 16.9 wk to 29.1 wk (HR, 0.47
(MGMT unmethylated) 25 Gy in 5 [95% CI, 0.29-0.76]; P = .0161
fractions In patients ≥60 y with KPS≥50, there was no difference in
survival (standard radiotherapy, 60 Gy [overall survival,
5.1 mo] vs short-course radiotherapy, 40 Gy [overall survival,
5.6 mo]; HR, 0.89 [95% CI, 0.59-1.36]; P = .57)59
In patients ≥50 y with KPS 50-70 or ≥65 y with KPS 80-100,
there was no difference in survival with 25 Gy radiotherapy
(overall survival, 7.9 mo) and 40 Gy radiotherapy (overall
survival, 6.4 mo); P = .9962
Temozolomide alone Temozolomide 100 mg/m2 once/d on d 1-7 in cycles of 1 wk In patients ≥65 with KPS ≥60 with MGMT promoter Grade 3/4 toxicities: neutropenia (16/195), lymphopenia
(MGMT methylated) on/1 wk off; dose increases or decreases in 25-mg/m2 steps methylation, treatment with temozolomide alone yielded (46/195), thrombocytopenia (14/195), liver enzyme
based on tolerability; duration, 6-mo course or median overall survival of 18.4 mo vs 9.6 mo with elevation (35/195), thromboembolic event (24/195),
150-200 mg/m2 orally once/d on d 1-5 of each 28-day radiotherapy alone (HR, 0.44 [95% CI, 0.27-0.70]; fatigue (24/195)63
cycle, ≤12 cycles P < .001); this was a noninferiority trial63
Best supportive care
Astrocytoma, IDH-mutant, non-codeleted
Grade 2
Radiotherapy followed 54 Gy in 30 Temozolomide 150-200 mg/m2 orally once/d on d 1-5 of No efficacy data available specific to this patient population; Grade 3/4 hematologic toxicity 15%, grade 3/4

© 2023 American Medical Association. All rights reserved.

by temozolomide fractions twelve 28-d cycles use of temozolomide regimen extrapolated from astrocytoma aminotransferase elevation 1%64,65
grade 3 literature
Radiotherapy followed 54 Gy in 30 Procarbazine 60 mg/m2 orally once/d on d 8-21, lomustine At a median follow-up of 9 y, median overall survival was Grade 3/4 toxicities included fatigue (8/125), weight loss

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by procarbazine, fractions 110 mg/m2 orally once on d 1, vincristine 1.4 mg/m2 IV 4.3 y for patients treated with radiotherapy alone vs 11.4 y (4/125), hematologic toxicity (64/125), nausea/vomiting
lomustine, and (maximum 2 mg) once/d on d 8 and d 29 for six 8-wk cycles for patients treated with radiotherapy followed by (7/125), hepatic toxicity (3/125)67
vincristine procarbazine, lomustine, and vincristine (HR, 0.38;
P = .01)66
Observationc
Grade 3
Radiotherapy followed 59.4 Gy in 33 Temozolomide 150-200 mg/m2 orally once/d on d 1-5 of In patients with astrocytoma grade 3, overall survival was Grade 3/4 toxicities: hematologic 15%, aminotransferase
by temozolomide fractions twelve 28-d cycles 82.3 mo with radiotherapy and temozolomide vs 46.9 mo elevation 1%64,65
with radiotherapy alone (HR, 0.64 [95% CI, 0.52-0.79];
P < .001)64

(continued)

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Review Clinical Review & Education

581
 582
Table 2. First-Line Treatment of Adult-Type Diffuse Glioma (continued)

Dose and frequency of administration

Treatment options Radiotherapy Chemotherapy Efficacy Adverse effectsa
Grade 4
Radiotherapy with or 60 Gy in 30 Concurrent temozolomide 75 mg/m2 orally once/d during No efficacy data available specific to this patient population; Grade 3/4 toxicities: hematologic (16%),50 transaminitis
without temozolomide fractions radiotherapy and use of temozolomide regimen extrapolated from astrocytoma (2%)64
followed by Adjuvant temozolomide 150-200 mg/m2 orally once/d grade 3 and glioblastoma literature
temozolomide on d 1-5 of 28-d cycle for 6-12 cycles
Oligodendroglioma, IDH-mutant, codeleted
Clinical Review & Education Review

Grade 2
Radiotherapy followed 54 Gy in 30 Procarbazine 60 mg/m2 orally once/d on d 8-21, lomustine At a median follow-up of 9 y, median overall survival was Grade 3/4 toxicities included fatigue (8/125), weight loss
by procarbazine, fractions 110 mg/m2 orally once on d 1, vincristine 1.4 mg/m2 IV 13.9 y for patients treated with radiotherapy alone vs not (4/125), hematologic toxicity (64/125), nausea/vomiting
lomustine, and (maximum 2 mg) once/d on d 8 and d 29 for six 8-wk cycles reached for patients treated with radiotherapy and (7/125), hepatic toxicity (3/125)
vincristine procarbazine, lomustine, and vincristine (HR, 0.21;
P = .03)66
Radiotherapy with or 54 Gy in 30 Concurrent temozolomide 75 mg/m2 orally once/d until No prospective efficacy data available specific to this patient Grade 3/4 toxicities included hematologic toxicity
without temozolomide fractions radiotherapy is completed population. Use of temozolomide regimen extrapolated from (16%),50 transaminitis (2%)64
followed by Adjuvant temozolomide 150-200 mg/m2 orally once/ astrocytoma and glioblastoma literature
temozolomide d on d 1-5 of each 28-d cycle, ≤12 cycles

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Observationc
Grade 3
Radiotherapy followed 59.4 Gy in 33 Procarbazine 60 mg/m2 orally once/d on d 8-21, lomustine Median overall survival 9.3 y radiotherapy alone vs 14.2 y Grade 3/4 hematologic toxicity (74/161), nausea (9/161),
by procarbazine, fractions 110 mg/m2 orally once on d 1, vincristine 1.4 mg/m2 IV radiotherapy + procarbazine, lomustine, and vincristine vomiting (10/161), neuropathy (3/161), allergic skin
lomustine, and (maximum 2 mg) once/d on d 8 and d 29 for six 6-wk cycles (HR, 0.60; 95% CI, 0.35 to 1.03; P = .06)68 reactions (2/161)69
vincristine
Procarbazine- 59.4 Gy in 33 Procarbazine 75 mg/m2 orally once/d on d 8-21, lomustine Median overall survival 7.3 y with radiotherapy alone vs Grade 3/4 toxicities: hematologic toxicity (80/144),
lomustine-vincristine fractions 130 mg/m2 orally once on d 1, vincristine 1.4 mg/m2 IV 13.2 y with radiotherapy + procarbazine, lomustine, and neurologic toxicity (cognitive or mood change, peripheral
(intensified) followed (no maximum) on d 8 and d 29 for four 6-wk cycles vincristine (HR, 0.61 [95% CI, 0.4 to 0.94]; P = .02)68 or autonomic neuropathy) (19/144), nausea/vomiting
by radiotherapy (13/144), hepatic toxicity (6/144), dermatologic toxicity
(6/144)70
Radiotherapy with or 59.4 Gy in 33 Concurrent temozolomide 75 mg/m2 orally once/d until No efficacy data available specific to this patient population; Grade 3/4 toxicities: hematologic (16%),50 transaminitis
without temozolomide fractions radiotherapy is completed use of temozolomide regimen was extrapolated from (2%)64
followed by Adjuvant temozolomide 150-200 mg/m2 orally once/ astrocytoma and glioblastoma literature
temozolomide d on days 1-5 of each 28-d cycle, ≤12 cycles
Abbreviations: IDH, isocitrate dehydrogenase; IV, intravenously; KPS, Karnofsky Performance Status; myelosuppression including neutropenia [8%], thrombocytopenia [4%-8%], hepatotoxicity). Data regarding
MGMT, O6-methylguanine-DNA-methyltransferase. the percent of patients affected were included when reported.

© 2023 American Medical Association. All rights reserved.

a b
Indicates adverse effects as reported in the corresponding clinical trial. Additional important adverse effects Treatment of IDH-wild-type tumors that do not meet molecular or histological criteria for glioblastoma is not
(by drug) include the following: for procarbazine (hypertensive crisis as result of monoamine oxidase inhibition, well-defined. Generally, recommendations for IDH-wild-type-glioblastoma may be followed, and participation in

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rash, abdominal pain, constipation, diarrhea, nausea, vomiting, myelosuppression, hepatotoxicity); for a clinical trial should be strongly considered.
lomustine (nausea, vomiting, myelosuppression, hepatoxicity, pulmonary toxicity); for vincristine (alopecia, c
Consider for patients with favorable prognostic factors: gross total resection, minimal neurologic deficits,
neuropathy [including autonomic neuropathy], hyponatremia, constipation, myelosuppression, ototoxicity, younger than 40 years of age.
bronchospasm); for temozolomide (constipation [18%-22%], nausea [36%-49%], vomiting [20%-29%],

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Glioblastoma and Other Primary Brain Malignancies in Adults
 Glioblastoma and Other Primary Brain Malignancies in Adults
reached [radiotherapy + procarbazine, lomustine, and vincris-
tine]; HR, 0.21; P = .03) (IDH-mutant 1p/19q non-codel [43 pa-
tients]; overall survival, 4.3 years with radiotherapy alone vs 11.4 years
for those who received radiotherapy + procarbazine, lomustine, and
vincristine; HR, 0.38; P = .01).66 Long-term survival analysis from
the European Organization for the Research and Treatment of Can-
cer (EORTC) 26951 and RTOG 9402 trials showed that adding pro-
carbazine, lomustine, and vincristine to radiotherapy lengthened
overall survival compared with radiation alone as first-line therapy
for anaplastic oligodendroglial tumors (EORTC 26951 [80 pa-
tients]; overall survival, 14.2 years vs 9.3 years; HR, 0.60 [95% CI,
0.35-1.03]; P = .06 and RTOG 9402 [125 patients]; overall survival,
13.2 years vs 7.3 years; HR, 0.61 [95% CI, 0.4-0.94]; P = .02).68 Both
EORTC 26951 and RTOG 9402 studies demonstrated a progression-
free survival of more than 30% at 20 years in patients with 1p/19q
codeletion, indicating that durable disease control was feasible with
this regimen. Procarbazine, lomustine, and vincristine also im-
proved overall survival for patients with IDH-mutant tumors with-
out 1p/19q codel,68 consistent with the results from RTOG 9802. Te-
mozolomide is an acceptable alternative to procarbazine, lomustine,
and vincristine.32 The phase 3 Trial on Concurrent and Adjuvant Te-
mozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma
(CATNON Intergroup Trial) showed that overall survival was im-
proved with the use of adjuvant temozolomide (median overall sur-
vival, 82.3 months vs 46.9 months; HR, 0.64 [95% CI, 0.52-0.79];
P < .001) when compared with patients who did not receive temo-
zolomide after radiation.64 It is currently unknown whether radia-
tion with temozolomide or radiation with procarbazine, lomustine,
and vincristine are more effective in treating patients with newly di-
agnosed 1p/19q codel glioma.
Progress has been made in delineating the pathobiology of IDH-
mutant glioma since the first report of IDH mutations in glioma.88
Production of the metabolite 2-hydroxyglutarate (2HG) by the mu-
tant IDH enzyme and subsequent accumulation of 2HG in tumor tis-
sue inhibits α-ketoglutarate-dependent enzymes, eliciting pro-
found effects on DNA methylation, gene expression, cellular
differentiation state, and the tumor microenvironment.86 Small mol-
ecule inhibitors of the mutant IDH enzyme have shown preliminary
activity against IDH-mutant lower-grade gliomas,89,90 and an IDH1
(R132H)-specific peptide vaccine induced specific therapeutic T
helper cell responses.91
Treatment of PCNSL
PCNSL is a rare hematologic malignancy confined to the brain, spi-
nal cord, and leptomeningeal or vitreoretinal space. The annual in-
cidence is 0.4 per 100 000, but incidence increases with age to 4
per 100 000 in patients older than 70 years.6 Immunodeficiency
is a known risk factor, but PCNSL also affects immunocompetent pa-
tients. Presenting neurologic symptoms develop over the course of
weeks to months and may be reversed with treatment. Unlike other
brain tumors discussed in this review, PCNSL is highly sensitive to
chemotherapy and radiation, and the goal of treatment is cure, al-
though approximately 33% to 60% of patients will relapse.92
The diagnosis of PCNSL is made with tumor biopsy. The asso-
ciation of more extensive tumor resection with improved survival
remains controversial. High-dose intravenous methotrexate, ad-
ministered at a dose between 3 to 8 g/m2 in at least 4 to 8 infu-
sions, is the most effective therapy and is included in several com-
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Review Clinical Review & Education
bination chemotherapy regimens. A randomized phase 2 trial of 79
patients with PCNSL showed a poorer radiographic response to high-
dose intravenous methotrexate alone (40%) than to high-dose in-
travenous methotrexate plus cytarabine (69%) (P = .01).93 Other
drug combinations include rituximab, methotrexate, procarba-
zine, and vincristine; methotrexate, temozolomide, and rituximab;
methotrexate, cytarabine, thiotepa, and rituximab; and rituximab,
methotrexate, carmustine, etoposide, and prednisone.7 Because of
high response rates, typically consisting of a greater than 80% to
90% radiographic response, methotrexate-based therapy is used
as first-line treatment even in older frail patients and those with
difficulty performing activities of daily living due to symptoms.
To reduce relapse rates, patients receive consolidation therapy
with either myeloablative thiotepa (alkylating therapy)–based con-
ditioning followed by autologous stem cell transplant, nonmyeloab-
lative chemotherapy (eg- with etoposide/cytarabine), or whole brain
radiation therapy.94-96 Delayed neurotoxicity, presenting with gait
imbalance and impaired cognition, affects approximately 60%
of patients treated with radiation.92 Approximately 36% to 62% of
patients relapse following initial responses to first-line therapy, usu-
ally within the first 2 years after treatment.93 Re-treatment with high-
dose intravenous methotrexate is appropriate for patients who ini-
tially responded to high-dose intravenous methotrexate–based
induction therapy. High-dose combination therapy followed by au-
tologous stem cell transplant, the Bruton tyrosine kinase inhibitor
ibrutinib, thalidomide derivatives (lenalidomide, pomalidomide), or
clinical trials should be considered for patients with relapsed or re-
fractory disease.7
Treatment of Malignant Meningiomas
Meningiomas are the most common primary CNS tumor in adults1;
however, more than 90% are benign (WHO grade 1)8 and either re-
quire no intervention or are curable with surgery or focal radiation.
Approximately 5% are WHO grade 2 (atypical), and 1% to 2% are
WHO grade 3 (malignant/anaplastic).8 Several molecular altera-
tions (eg, TERT promoter mutation, CDKN2A/B deletion, loss of tri-
methylation of lysine 27 of histone 3) are associated with worse prog-
nosis, and more complex genomic or integrated molecular-
morphologic scores outperform traditional histopathological WHO
grading in their ability to predict outcome.97 Meningiomas are more
common in women (incidence approximately 12.76 per 100 000 vs
5.79 per 100 000 in men)1 and may be associated with underlying
cancer predisposition syndrome such as neurofibromatosis 2.
Meningiomas that are small (<3 cm), asymptomatic, and lack
peritumoral edema can be monitored radiographically. A typical sur-
veillance schedule is repeat MRI at 3, 6, and 12 months after diag-
nosis, every 6 to 12 months for 5 years, then every 1 to 3 years.32 In
a meta-analysis of 2130 patients with incidental meningioma and a
follow-up of 49.5 months, 1040 (50.7%) were initially observed with-
out intervention. Of these, 220 were recommended for interven-
tion, either resection or stereotactic radiosurgery, a precise and fo-
cal form of radiation during the follow-up period, most for
radiographic progression.98 Asymptomatic meningiomas that re-
quire intervention but are not amenable to surgery due to location
may be treated with stereotactic radiosurgery. In a retrospective,
multicenter matched-cohort study of patients with asymptomatic,
skull-based meningiomas that were propensity score–matched for
age, tumor volume, and follow-up (n = 110 patients in each cohort),
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tumor control was achieved in 98.2% and 61.8% of the stereotac-
tic radiosurgery and active surveillance cohorts, respectively.99
Symptoms of meningiomas are generally related to their loca-
tion. Meningiomas that are large, rapidly enlarging, symptomatic, as-
sociated with edema, or appear to be infiltrating the parenchyma
should be resected. Total resection is an independent positive prog-
nostic factor for progression-free and overall survival and should be
attempted.100 Adjuvant fractionated radiation therapy is recom-
mended for all grade 3 and incompletely resected grade 2
meningiomas.32 In the event of recurrence, which occurs in 50% to
90% of patients with grade 2 and 3 meningiomas,100,101 further re-
sectionorradiationtherapymaybeconsidered.Antiangiogenicagents,
such as bevacizumab and sunitinib, and the focal adhesion kinase in-
hibitor GSK2256098 showed antitumor activity in small single group
of retrospective studies.102-105 A small percentage of atypical or ma-
lignant meningiomas may have increased expression of PD-L1, an in-
creased tumor mutational burden, or deficiencies in mismatch repair
may be present. Responses to immunotherapy have been described
in these settings.106,107
Treatment of Malignant Ependymomas
Ependymomas are a heterogenous group of tumors arising from the
ependymal lining of the brain. These tumors differ in their biology ac-
cording to patient age, tumor location, histology, and molecular fea-
tures. Because malignant ependymomas are rare, few clinical trials of
therapies for malignant ependymomas exist. In addition, 9 distinct ep-
endymoma subgroups were identified recently, and it is unclear
whether current treatments apply across the 9 subgroups.108,109 Sur-
gery is a first-line treatment for intracranial ependymomas, and gross
total resection is associated with improved survival.110 Postoperative
radiation is recommended for WHO grade 3 tumors and incompletely
resected grade 2 tumors.32 Intracranial ependymomas in adults with
spinal or cerebrospinal fluid dissemination should be treated with cra-
niospinal radiation. Chemotherapy is reserved for recurrence after lo-
cal treatment options (reoperation, reirradiation). Retrospective co-
hort studies in pediatric and adult ependymoma patients did not
demonstrate survival benefit with chemotherapy,108 but temozolo-
mide, etoposide, and bevacizumab may benefit a subset of patients.9
Prognosis
The 5-year survival following diagnosis of a malignant brain tumor
is approximately 36%. Older patients have poorer survival than
younger patients. Survival rates by age are approximately 71.5% for
patients aged 15 to 39 years and 21% for patients aged 40 years and
older.1 The median overall survival for patients with IDH-wild-type
glioblastoma is 12 to 21 months, and approximately 7% survive 5
years.50,51 Patients with IDH-mutant 1p/19q non-codel tumors have
a median overall survival of 7-8 years64,66; whereas patients with 1p/
19q-codel oligodendrogliomas have a median overall survival of 13
to 14 years after chemoradiation.66,68 Recurrence rates of malig-
nant meningiomas are 50% to 90% with a 5-year overall survival
of 20% to 50%.100,101 The 10-year overall survival of patients with
ependymal tumors is approximately 80%, but prognosis depends
on patient age, tumor grade, tumor location, and site-specific mo-
lecular genetics.108 PCNSL is potentially curable with chemo-
therapy, and 10-year survival for PCNSL is approximately 30%.1,111
Limitations
This review has some limitations. First, this was not a systematic re-
view. Second, the quality of included studies was not assessed. Third,
some relevant reports may have been missed. Fourth, the review is
limited by quality of the evidence. Fifth, this review did not discuss
the following tumor types: pediatric-type diffuse gliomas (such as
histone-mutant gliomas, which can present in adults), astrocytic glio-
mas, glioneuronal tumors, neuronal tumors (which are relatively rare
and occur more frequently in children and young adults), or pri-
mary brain tumors in patients with HIV/AIDS.
Conclusions
The incidence of primary malignant brain tumors is approximately
7 per 100 000 individuals and approximately 49% of primary ma-
lignant brain tumors are glioblastomas. Most patients die from pro-
gressive disease. First-line therapy for glioblastoma is surgery fol-
lowed by radiation and the alkylating chemotherapeutic agent
temozolomide.

ARTICLE INFORMATION
Accepted for Publication: January 2, 2023.
Conflict of Interest Disclosures: Dr Schaff
reported nonfinancial support from Merck
Research (drug only; for a clinical trial pertaining to
IDH-mutant glioma) and BTG Specialty
Pharmaceuticals; research support (financial) for a
clinical trial related to use of glucarpidase in
treatment of central nervous system lymphoma;
personal fees from DebioPharm (consulting work
outside the submitted work); membership on the
scientific advisory board for BTG; and a patent
pending for low-dose glucarpidase after
methotrexate. Dr Mellinghoff reported personal
fees (advisory board services) from Roche
Therapeutics, Servier Pharmaceuticals, Prelude
Therapeutics, Black Diamond Therapeutics, Agios,
Debiopharm Group, Voyager, and Novartis; and
grants from General Electric and Puma
Biotechnology outside the submitted work.
Funding/Support: This article was supported in
part by grants from NIH (1R35NS105109-01)
to Dr Mellinghoff and a support grant
(NIH-P30-CA08748) to Memorial Sloan Kettering
Cancer Center.
Role of the Funder/Sponsor: NIH had no role in
the design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
Additional Contributions: The authors would like
to acknowledge the following individuals from
Memorial Sloan Kettering Cancer Center: Lisa
Modelevsky, PharmD, BCOP, Department of
Pharmacy; Miguel Foronda Alvaro, PhD,
Department of Neurology; and Tejus A. Bale, MD,
PhD, Department of Pathology, for their
contributions to the editing of this article, and
Samantha Welker, MA, Department of Marketing
and Communications for assistance with medical
illustrations. These individuals were not
compensated in association with their
contributions to this article. Written permission was
obtained to include them in this acknowledgment
section.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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