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Developed for Cure Brain Cancer Foundation
by Dr Ruth Hadfield & Dr Julia Bates
April 2018
68
Cure Brain Cancer Foundation ............................................................................................................ 1
Literature Review 2018 ............................................................................................................... 1
Abbreviations .......................................................................................................................................... 6
Introduction ............................................................................................................................................ 7
Executive Summary ................................................................................................................................. 7
Key advances in brain cancer research over the past 5 years ............................................................ 8
Methodology ........................................................................................................................................... 8
Search terms ....................................................................................................................................... 8
Types of brain tumours ........................................................................................................................... 9
Aetiology ............................................................................................................................................... 11
Risk factors ........................................................................................................................................ 11
Family history .................................................................................................................................... 11
Incidence and survival rates.................................................................................................................. 12
Molecular biology of brain cancer ........................................................................................................ 13
Key points .......................................................................................................................................... 13
Introduction ...................................................................................................................................... 13
Molecular biology of malignant gliomas ........................................................................................... 13
Molecular biology of diffuse astrocytic and oligodendroglial tumours ........................................ 14
The p53 pathway....................................................................................................................... 16
The RB pathway ........................................................................................................................ 18
EGFR and the PI3K & MAPK pathways ...................................................................................... 18
IDH1/2 mutations...................................................................................................................... 18
PTEN mutations and deletions .................................................................................................. 19
Epigenetic modifications and the role of MGMT ...................................................................... 20
BRAF mutations ......................................................................................................................... 20
Chromosome 1p/19q co-deletion ............................................................................................. 20
TERT/ATRX mutations ............................................................................................................... 21
Histone H3 mutations ............................................................................................................... 22
CIC/FUBP1 mutations ................................................................................................................ 22
Gene fusions ............................................................................................................................. 22
MicroRNAs ................................................................................................................................ 22
Angiogenesis and VEGF ............................................................................................................. 22
Molecular biology of pilocytic astrocytomas ................................................................................ 22
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Molecular biology of ependymal tumours.................................................................................... 23
Molecular biology of diffuse intrinsic pontine glioma .................................................................. 23
Molecular biology of H3-K27M-mutant diffuse midline glioma ................................................... 24
Molecular biology of other tumour types......................................................................................... 24
Medulloblastomas ........................................................................................................................ 24
Meningiomas ................................................................................................................................ 24
Detection, diagnosis, and prognosis ..................................................................................................... 26
Key points .......................................................................................................................................... 26
Symptoms ......................................................................................................................................... 26
Diagnosis: current practice guidelines .............................................................................................. 27
Australian guidelines ..................................................................................................................... 27
European guidelines...................................................................................................................... 28
American guidelines ...................................................................................................................... 31
UK guidelines................................................................................................................................. 31
Other recent guidelines ................................................................................................................ 32
Integrated diagnosis: the role of molecular markers ....................................................................... 33
2016 WHO Classification System for CNS Tumours ...................................................................... 34
Diagnostic tools ................................................................................................................................. 35
Radiology and imaging .................................................................................................................. 35
Gene panels and DNA-methylation profiling ................................................................................ 36
Prognostic factors ............................................................................................................................. 37
Prognostic biomarkers .................................................................................................................. 37
MGMT promoter methylation .................................................................................................. 37
MicroRNA .................................................................................................................................. 40
Stem cell markers ...................................................................................................................... 41
Blood-derived biomarkers ........................................................................................................ 41
Treatment ............................................................................................................................................. 42
Key points .......................................................................................................................................... 42
Introduction ...................................................................................................................................... 43
Surgical management ....................................................................................................................... 43
Surgical resection .......................................................................................................................... 43
For low-grade astrocytoma (LGA): ............................................................................................ 43
For high-grade astrocytoma (HGA): .......................................................................................... 44
For oligodendrogliomas (OG) or oligoastrocytoma (OA): ......................................................... 44
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Biopsy versus resection ................................................................................................................. 45
Image-guided surgery ................................................................................................................... 45
Awake craniotomy .................................................................................................................... 45
Laser interstitial thermal therapy (LITT) ....................................................................................... 46
Optical Coherence Tomography (OCT) ......................................................................................... 46
Chemotherapy .................................................................................................................................. 46
Temozolomide .......................................................................................................................... 46
Chemoradiotherapy .................................................................................................................. 47
Carmustine wafers .................................................................................................................... 47
Other chemotherapy agents ..................................................................................................... 47
Drug repurposing ...................................................................................................................... 47
Targeted chemotherapy ........................................................................................................... 48
Radiation therapy ............................................................................................................................. 48
Timing of radiotherapy ................................................................................................................. 48
Hypofractionated IMRT and VMAT ............................................................................................... 49
Hypofractionated stereotactic radiosurgery ................................................................................ 49
Whole brain radiotherapy combined with stereotactic radiosurgery .......................................... 50
Whole brain radiotherapy combined with other therapies ......................................................... 50
The use of biomarkers to predict response to radiotherapy .................................................... 50
Tumour-treating fields ...................................................................................................................... 50
Targeted therapies ............................................................................................................................ 51
Antibodies ..................................................................................................................................... 56
EGFR inhibitors .......................................................................................................................... 56
Anti-angiogenic agents.............................................................................................................. 56
Antibody drug–conjugates (ADCs) ............................................................................................ 56
Other emerging targeted therapies .............................................................................................. 56
Immune therapies ............................................................................................................................. 57
Active immunotherapy ............................................................................................................. 57
Immune checkpoint inhibitors .................................................................................................. 58
Vaccines .................................................................................................................................... 59
CAR T cell-therapy ..................................................................................................................... 60
Personalised medicine: the use of predictive biomarkers ........................................................ 61
Salvage therapies .............................................................................................................................. 61
Emerging therapies ........................................................................................................................... 61
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Gene therapy ................................................................................................................................ 62
Toca 511/Toca FC .......................................................................................................................... 63
Nanoparticles ................................................................................................................................ 63
Stem cell therapy .......................................................................................................................... 66
Disruption of the blood–brain-barrier (BBB) ................................................................................ 66
Tumour microtubules ................................................................................................................... 67
CRISPR/CAS9 for genomic editing therapy ................................................................................... 67
Other emerging agents ................................................................................................................. 67
Holistic and alternative treatments .................................................................................................. 68
Tumour-specific treatment and outcomes ....................................................................................... 68
Glioblastoma ................................................................................................................................. 68
Diffuse Intrinsic Pontine Glioma (DIPG) ........................................................................................ 69
Ependymoma ................................................................................................................................ 69
Medulloblastoma .......................................................................................................................... 69
Meningioma .................................................................................................................................. 70
Oligodendroglioma ....................................................................................................................... 70
Oligoastrocytoma .......................................................................................................................... 70
Response evaluation ............................................................................................................................. 70
Pseudoprogression ........................................................................................................................... 71
Summary ............................................................................................................................................... 71
Tables & Figures .................................................................................................................................... 73
Appendix 1 ............................................................................................................................................ 74
Example PubMed search strings used for searches: ..................................................................... 74
Appendix 2 ............................................................................................................................................ 75
Clinical trials currently underway in Australia .................................................................................. 75
References ............................................................................................................................................ 77
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Abbreviation Definition
ALT Alternative Lengthening of Telomeres ATRX α-thalassemia/mental retardation syndrome X-linked BBB Blood–Brain Barrier bFGF basic Fibroblast Growth Factor CAR T cells Chimeric Antigen Receptor T cells CI Confidence interval CNS Central Nervous System CT Computed tomography DIPG Diffuse Intrinsic Pontine Glioma DWI Diffusion-weighted imaging EGFR Epidermal Growth Factor Receptor EMSO European Society for Medical Oncology GBM Glioblastoma multiforme GWAS Genome-Wide Association Studies HGG High-Grade Glioma HR Hazard ratio IDH Isocitrate dehydrogenase 1 KPS Karnofsky Performance Status LGG Low-Grade Glioma LITT Laser interstitial thermal therapy LOH Loss of Heterozygosity mAbs monoclonal antibodies MAPK Mitogen-Activated Protein Kinase miRNA micro-RNA MRI Magnetic Resonance Imaging NGS Next-generation sequencing NICE National Institute for Health and Care Excellence OCT Optical Coherence Tomography OR Odds ratio OS Overall Survival PET Positron Emission Tomography PDGF Platelet Derived epidermal Growth Factor PI3K/Akt Phosphatidylinositol 3-Kinase PCNSL Primary CNS lymphoma PFS Progression-Free Survival PNET Primitive Neuroectodermal PTEN Phosphatase and TENsin homolog protein RB1 Retinoblastoma protein 1 SRS Stereotactic RadioSurgery TERT Telomerase Reverse Transcriptase TTFields Tumour-treating fields TMZ Temozolomide VEGF Vascular Endothelial Growth Factor WBRT Whole Brain Radiation Therapy WHO World Health Organisation
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The aim of this descriptive literature review is to provide a high-level overview of new strategies,
developments and milestones in brain cancer research. The review focuses on gliomas and
describing the current state of research globally, and emerging areas of research that have potential
to more immediately improve patient survival. This will provide a basis for future, strategic decision
making for the Cure Brain Cancer Foundation’s research strategy.
The current review (2018) represents an update of the review undertaken in 2014.
Every year there are approximately 1,250 deaths from brain cancer in Australia.(2) The most recent
Australian data shows that people diagnosed with brain cancer have an estimated 20% five-year
survival rate, far poorer that the estimated 68% for all cancers combined.(3) The most common type
of malignant brain tumour glioblastoma (GBM), is associated with five-year relative survival rates of
only 4.6%.(2)
Since the last literature review in 2014, there has been a sharp increase in the volume of research on
GBM resulting in exciting new developments (Figure 1). The volume of research has increased
exponentially, and breakthroughs have been made in characterising key genetic alterations and
epigenetic profiles associated with the different types of gliomas. This in turn has resulted in the
publication of new WHO tumour classification recommendations in 2016. The new system combines
molecular biomarkers and histological features, allowing for more accurate diagnosis and potentially
more targeted treatment.
Figure 1: Number of publications on the topic of glioblastoma in PubMed showing rapid growth of interest in this field of research.
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In October 2015, the use of tumour-treating fields (TTFields or OptuneTM)—which delivers
low-intensity, intermediate-frequency, alternating electric fields via a specialized helmet
worn to inhibit tumour growth—in combination with temozolomide for the treatment of
adults with newly diagnosed glioblastoma was approved by the US Food and Drug
Administration (FDA). TTFields is also now FDA-approved for treatment of recurrent
glioblastoma as a monotherapy after surgical and radiation options have been exhausted.
In May 2016, the World Health Organization (WHO) published an official restructuring of the
classification of tumours of the central nervous system to combine molecular biomarkers
and histological features in an integrated diagnosis.
The diagnostic biomarkers used in the 2016 WHO classification of gliomas include: IDH1/2
mutations, 1p/19q co-deletion, H3F3A or HIST1H3B/C K27M (H3-K27M) mutations, and
C11orf95–RELA fusions. Other diagnostically relevant biomarkers include: loss of nuclear
ATRX expression, TERT-promoter mutations, KIAA1549–BRAF fusions, the BRAF-V600E
mutation, and the H3F3A-G34 mutation.
Genome-wide association studies (GWAS) have revealed some of the key characteristic
genetic alterations and epigenetic profiles associated with the different types of gliomas. A
2017 meta-analysis of existing GWAS and two new GWAS identified five new loci associated
with glioblastoma.
Advanced imaging techniques such as diffusion-weighted imaging (DWI) are being
increasingly used to more accurately diagnose gliomas and to distinguish pseudoprogression
from true tumour progression.
Predictive biomarkers for targeted therapies in patients with CNS tumours are also
emerging; for example, MGMT-promoter methylation is predictive of benefit from alkylating
chemotherapy in patients with IDH-wild-type glioblastoma.
Immunotherapies such as peptide vaccines, dendritic cell vaccines, and immune checkpoint
inhibitors (anti-PD-1 and anti-CTLA-4) have been studied in clinical phase II/III trials and at
least three immunotherapies are in phase III clinical trials.
Other emerging therapeutic strategies (including gene therapy, oncolytic virotherapy,
nanoparticles, stem cell therapy, and blood–brain barrier disruption) are being investigated
for the treatment of glioblastoma.
Specific searches (derived from the 2014 review) related to each section of this review were
conducted in PubMed in March 2018 using the search terms outlined in . In order to
ensure a focus on only high quality studies, inclusion criteria were mainly restricted to:
Meta-analyses
Systematic reviews
Randomised controlled trials (RCTS)
Clinical practice guidelines
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Only studies published in English and conducted in humans published between March 2013 and
March 2018, and with an abstract available, were included for review. Examples of the PubMed
search strings used are included in Appendix 1.
PubMed abstracts were read, and relevant reviews sourced. Once relevant publications were
sourced and read, additional papers were identified from reference lists and included if they were
relevant and high quality studies.
A search of the Cochrane Library was made using the following search terms: brain cancer, brain
tumor, brain tumour, GBM, glioma, and glioblastoma. A search of the Australian Clinical Trials
Registry was made using the terms brain, cancer and currently recruiting.
There are more than 120 types of brain and central nervous system (CNS) tumours. With the advent
of new technologies (such as next-generation sequencing and proteomics), the classification of
tumours is constantly evolving as further information about the molecular changes occurring at each
step of the tumorigenesis process is acquired. (4)
Based on this molecular information, the World Health Organisation (WHO) published a major
restructuring of the classification of tumours of the CNS in May 2016. This classification system
integrates molecular information and histology to improve diagnostic accuracy. (5)
Currently, most medical and research institutions use the WHO classification system of CNS tumours.
The WHO classifies brain tumours by cell origin and their level of aggressiveness (i.e., from the least
aggressive or benign to the most aggressive or malignant). Some tumour types are graded from
Grade I (least malignant) to Grade IV (most malignant); however, there are variations in grading
systems, depending on the tumour type.
The predominant types of CNS tumours in adults and children are listed alphabetically in Box 1. The
changing relative distribution by age is shown in Figure 2.
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Box 1. Types of CNS tumours.
• Acoustic Neuroma
• Astrocytoma: o Grade I – Pilocytic Astrocytoma o Grade II – Low-grade Astrocytoma o Grade III – Anaplastic Astrocytoma o Grade IV – Glioblastoma (GBM)
• Chordoma
• CNS Lymphoma
• Craniopharyngioma
• Other Gliomas: o Brain Stem Glioma o Ependymoma o Mixed Glioma o Optic Nerve Glioma o Subependymoma
• Medulloblastoma
• Meningioma
• Metastatic Brain Tumours
• Oligodendroglioma
• Pituitary Tumours
• Primitive Neuroectodermal (PNET)
• Other Brain-Related Conditions
• Schwannoma
More common in children than in adults:
• Brain Stem Glioma
• Craniopharyngioma
• Ependymoma
• Juvenile Pilocytic Astrocytoma (JPA)
• Medulloblastoma
• Optic Nerve Glioma
• Pineal Tumour
• Primitive Neuroectodermal Tumours (PNET)
• Rhabdoid Tumour
*From http://braintumor.org/brain-tumor-information/understanding-brain-tumors/tumor-types/
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Figure 2: New cases of brain and other CNS cancer, by site and life stage, 2013 (AIHW ACD 2013)
There is little known about the underlying cause of brain cancer. The only established risk factor is
ionising radiation, demonstrated in studies of children receiving cranial irradiation for cancer
therapy and Tinea capitis, and in individuals exposed to atomic bombs and nuclear weapons testing.
(6) A higher incidence has also been observed with increasing age and in men.
There is no clearly established link between an increased risk of glioma and exposure to mobile
phone use, head injury, foods containing N-nitroso compounds, aspartame, occupational risk factors
or pesticides. (6, 7)
Glioma risk is inversely associated with the presence of atopic diseases such as asthma, eczema, and
hay fever. (8) A 2016 meta-analysis confirmed that having: ‘a history of respiratory allergies was
associated with an approximately 30% lower glioma risk, compared to not having respiratory
allergies (mOR: 0.72, 95% CI: 0.58–0.90). This association was similar when restricting to high-grade
glioma cases. Asthma and eczema were also significantly protective against glioma.’ (9) While it has
been suggested that the protective effects of these atopic diseases could reflect an effect of
heightened immune surveillance on brain tumour development, the underlying mechanism(s)
remain unclear.
A family history of glioma is rarely observed but, when present, is associated with a two-fold
increase in the risk of developing glioma. Genome-wide association studies (GWAS) have identified a
few susceptibility variants for glioblastoma (GBM) and other gliomas, such as 20q13.33 (RTEL),
5p15.33 (TERT), 9p21.3 (CDKN2BAS), 7p11.2 (EGFR), 8q24.21 (CCDC26), and 11q23.3 (PHLDB1), but
these genes are only weakly associated with glioma. (7)
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For GBM, a 2017 meta-analysis of existing GWAS and two new GWAS identified five new loci: p31.3
(rs12752552), 11q14.1 (rs11233250), 16p13.3 (rs2562152), 16q12.1 (rs10852606) and 22q13.1
(rs2235573). (10) The authors also identified eight loci for non-GBM tumours: 1q32.1 (rs4252707),
1q44 (rs12076373), 2q33.3 (rs7572263), 3p14.1 (rs11706832), 10q24.33 (rs11598018), 11q21
(rs7107785), 14q12 (rs10131032) and 16p13.3 (rs3751667), indicating that genetic susceptibility to
GBM and non-GBM tumours is distinct. Currently identified risk variants for glioma account for
around 27% and 37% of the familial risk of GBM and non-GBM tumours, respectively. (10)
Having one of the following hereditary disorders may also increase the risk for brain cancer (11):
Neurofibromatosis
Tuberous sclerosis
Von Hippel Lindau disease
Familial Polyposis (Turcot Syndrome)
Li-Fraumenti
Lynch syndrome
Every year on average 1,750 new cases of brain cancer will be diagnosed in Australia and 1,250
people will die from brain cancer. (2)
From 2009 to 2013, Australians diagnosed with brain cancer had around a 20% chance of five-year
survival, compared to a survival rate of 68% for all cancers combined in the same period (Figure 3).
(3) GBM, the most common type of malignant brain tumour, is associated with the lowest five-year
relative survival rates at only 4.6%. (3) Five-year relative survival was highest for ependymal tumours
(81%) and oligodendrogliomas (76%).
In Australia, brain cancer kills more children than any other disease and brain cancer kills more
people under 40 than any other cancer. (2)
Figure 3: Five-year survival rate (%) from 1984 to 2013. Source data: AIHW. (3)
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70
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1984-1988 1989-1993 1994-1998 1999-2003 2004-2008 2009-2013
Brain All cancers combined
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Over the last decade, genome-wide molecular-association studies have revealed some of the
key characteristic genetic alterations and epigenetic profiles associated with the different
types of gliomas.
The most common genetic alterations found in gliomas include: IDH1/2 mutations, 1p/19q
co-deletion, H3F3A or HIST1H3B/C K27M (H3-K27M) mutations, and C11orf95–RELA fusions.
Other relevant alterations include: loss of nuclear ATRX expression, TERT-promoter
mutations, KIAA1549–BRAF fusions, the BRAF-V600E mutation, and the H3F3A-G34
mutation.
The major signalling pathways involved in glioblastoma pathogenesis include the
PI3K/AKT/mTOR, Ras/RAF/MEK/MAPK, Rb, p53, Wnt, TGF, and UPR pathways; these
pathways regulate cell proliferation, adhesion and migration, invasion, angiogenesis, cell
survival, and stemness.
Such information on the unique molecular changes present in CNS tumours is important not
only for diagnosis, but for developing novel and more targeted therapies.
A characteristic of all cancer cells is the presence of multiple changes at the molecular or DNA level
that drive the development and progression of the tumour.(12) These may include gene deletions,
chromosomal aberrations, single DNA base substitutions or mutations, DNA methylation or
epigenetic modifications. Until recently, the molecular basis of brain cancer has been poorly
understood, especially compared to other types of cancer. In the past few years, however, there has
been a global effort to describe and understand the genetic abnormalities present in brain
tumours.(13, 14) As a result, some of the key characteristic genetic alterations and epigenetic
profiles associated with the different types of CNS tumours have been revealed.(15)
The most common type of primary malignant brain tumour, accounting for around 70–80% of
patients, is malignant glioma.(7) The molecular causes of malignant glioma are highly variable or
‘heterogeneous’ between individual patients,(7) even within each subset.(16)
According to the 2016 WHO classification system, which combines molecular and histological
features, gliomas are currently classified as (5):
Diffuse astrocytic and oligodendroglial tumours:
IDH-mutant astrocytic gliomas (WHO grades II–IV)
IDH-mutant and 1p/19q-codeleted oligodendroglial tumours (WHO grades II–III)
IDH-wild-type GBMs (WHO grade IV; which typically manifest as primary GBMs)
IDH-mutant GBMs (WHO grade IV)
Histone H3-K27M (H3-K27M)-mutant diffuse midline gliomas (WHO grade IV)
Oligoastrocytomas (NOTE: according to the 2016 WHO classification, the diagnosis
of oligoastrocytoma is discouraged; only exceptional cases that cannot be
conclusively tested for IDH mutation and 1p/19q co-deletion that show a mixed
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oligoastrocytic histology can still be classified as oligoastrocytoma, not otherwise
specified).
Other astrocytic tumours
Ependymal tumours
Subependymomas (WHO Grade I)
Myxompapillary ependymomas (WHO Grade I)
Ependymomas (WHO Grade II)
RELA-fusion-positive ependymomas (WHO Grades II or III)
Anaplastic ependymomas (WHO Grade III)
Other gliomas
Astroblastoma
Angiocentric glioma (WHO Grade I)
Chordoid glioma of third ventricle (WHO Grade II) (5, 15)
Glioblastoma (GBM) accounts for 82% of cases of malignant glioma, while oligodendrogliomas
account for only around 2% of primary malignant brain tumours.(7, 17) In approximately 90% of
cases, GBM arises ‘de novo’, without evidence of a progressive pathway or precursor lesions; this is
termed primary GBM. Primary GBM tends to occur in patients over 45 years. In patients under 45
years, a progressive pathway from astrocytoma to anaplastic astrocytoma, and then to secondary
GBM is typical (Figure 4). Secondary GBM accounts for ~10% of all GBM cases.
Figure 4: Pathways to glioblastoma. Adapted from Hays et al., 2017. (18)
There are many molecular or genetic pathways that may result in primary GBM pathogenesis;
however the most frequent can be grouped into the p53 pathway, the RB1 pathway, the MAPK
pathway, and the P13K pathway. (19) The Cancer Genome Atlas Research study used integrated
analyses of multi-dimensional genomic data to identify deregulation of the RB1, p53 and
RTK/RAS/P1(3)K pathways as requisite events in the pathogenesis of most, if not all, GBM tumours.
(12)
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For secondary GBM, the most frequent pathways and genetic alterations include TP53 mutation
and/or loss of chromosome 17p, IDH1 and IDH2 mutations, and loss of chromosomes 1p, 9p, 19q,
10q (alone or in combination) (
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Figure 6). (19) As for primary GBM, the RB1 pathway is also common. The PTEN mutation is also a
common feature of both primary and secondary GBM.
Figure 5: Common pathways to primary and secondary glioblastoma (GBM), and pilocytic astrocytoma (PA). Adapted from Gupta et al., 2012. (19)
In recent years, more signalling pathways that contribute to GBM development have been
identified; these pathways regulate cell proliferation, adhesion and migration, invasion,
angiogenesis, cell survival, and stemness (
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Figure 6). (20)
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Figure 6: Novel signalling pathways identified to contribute to glioblastoma (GBM) development. From Cai & Sughrue (2018). (20)
Tumour suppressor p53 is a protein encoded by the chromosome 17p gene TP53. The protein is
mutated in around 50% of all human cancer tumours and is responsible for the transcription of
multiple genes involved in carcinogenesis signalling pathways. (21, 22) For example, the p53 protein
is responsible for the transcription of genes involved in apoptosis, angiogenesis, DNA repair,
metabolism, and oxidative stress. (22)
Wild-type p53 is a 393 amino acid protein with four domains. Around 95% of all known p53
mutations are found in the DNA-binding domain. Mutations that occur in the part of the p53 protein
involved in DNA binding (codons 248 and 273) are known as class I mutations. Those that occur in
areas that are critical to the conformational structure of the DNA binding interface are class II
mutations (codons 175, 245, 249 and 282). Class II mutations generate a more severe pathological
phenotype than class I mutations. The effects of different p53 mutations on GBM are summarised in
Table 1.
In GBM, the most commonly observed alterations to the p53 pathway include p53 mutations (30%),
ARF deletions (55%), MDM2 amplification (11%), and MDM4 amplification (4%). (12) These
disruptions to the p53 pathways are observed in 78% of GBM tumours implying a pivotal role for p53
in disease progression. (12) P53 also plays a pivotal role in regulating stem cell proliferation, survival
and differentiation.
In recent studies, micro-RNAs (miRNAs) transcribed from p53 have been shown to alter the
expression of genes involved in cell cycle arrest, apoptosis and cellular senescence. MiRNAs are
small RNA sequences (19–25 nucleotides). In glioma tumours, the miRNA-34 family is frequently
dysregulated. Studies have shown that miR-34a is downregulated in glioma tissue compared to
normal brain tissue.(22, 23) In contrast, upregulation of miR-34a was shown to reduce glioma
proliferation, induce apoptosis and limit tumour growth.(22)
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In paediatric tumours, mutations of the p53 gene are also common, with an incidence of between
35–50%, which is comparable to the incidence in adult tumours. A specific p53 mutation of amino
acid number 72 (Arginine to Proline) is common in both adult and paediatric astrocytomas. (21)
Although there is a large body of knowledge regarding p53, considerable research efforts are still
required into how p53 mutations impact glioma pathogenesis.
Table 1: P53 mutations and their impact on glioblastoma (GBM). From England et al., 2013. (22)
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The retinoblastoma protein (RB1) is a tumour suppressor protein encoded by the gene Rb on
chromosome 13. This protein is of central importance in cell cycle regulatory processes. RB1
functions in the RB pathway, which is often functionally inactivated in a large majority of human
cancers.
Another gene, CDKN2A (also called INK4a/ARF), which is deleted in many cancers including GBM,
encodes the protein p16, a key inhibitor of the cell cycle via RB pathway signalling. (12, 24) One
study showed 77% of glioma tumour samples harboured RB1 pathway aberrations with
chromosome 9 deletions of CDKN2A (55%), CDKN2B (53%) and CDK4 (14%). (24)
In addition, hypermethylation-mediated silencing of RB1 and CDKN2A is a common observation in
primary GBM. (24)
Overexpression of the epidermal growth factor receptor (EGFR, also called oncogene ErbB, ErbB1,
HER1) is a feature of approximately 60% of primary GBM tumours, (25) and EGFR gene amplification
is detectable in ~40% of IDH (isocitrate dehydrogenase 1)-wild-type GBMs. (15) In contrast, EGFR is
overexpressed in only 10% of secondary glioblastomas.
EGFR is a transmembrane protein encoded on chromosome 7 that belongs to the tyrosine kinase
superfamily. Upon ligand binding, the EGFR receptor converts from an inactive form to an active
dimer comprised of either two EGFR monomers paired together (homodimeric form) or EGFR paired
with another EGFR family member such as HER2, HER3, or HER4 (heterodimeric form). (26)
EGFR activation, following ligand binding and phosphorylation of the intracellular tyrosine kinase
domain, initiates signal transduction (27); the downstream signalling pathways include the mitogen-
activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K/Akt) and the SRC/FAK
pathways. (25, 26, 28) Activation of these signal transduction cascades leads to increased cell
proliferation, angiogenesis, and reduced apoptosis.
Approximately 10 different classes of EGFR mutations that commonly occur in GBM tumours have
been described. Missense mutations in the EGFR extracellular domain are found in ~7% of primary
GBM tumours. (26) Mutations or amplifications of the EGFR gene play a key role in many cancers
and are commonly seen in primary GBM and rarely in secondary GBM. (25, 29)
EGFRvIII is the most frequently observed variant (present in 24–67% of tumours). (27, 28, 30)
EGFRvIII has a large portion of the extracellular domain absent, due to a deletion in exons 2–7 of the
gene. Despite the deletion, EGFRvIII can still dimerise and phosphorylate, and is therefore still active;
studies have shown this variant EGFR form can enhance cell growth, increases PI3K activity and is
oncogenic. (13, 28) While there is evidence that EGFRvIII is a marker for poor prognosis, the exact
mechanism by which the mutation confers oncogenicity is yet to be fully understood. (26)
The discovery of IDH mutations in most WHO grade II and III gliomas was key to understanding its
pathogenesis. (15) Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are enzymes that catalyse the
oxidative decarboxylation of isocitrate to -ketoglutarate. The genes for the enzymes are located on
chromosomes 2q and 15q, respectively. Consequently, IDH mutation causes a reduction in the
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catalysis of this reaction, due to a change in substrate preference, and this results in aberrant DNA
and histone methylation, leading to hypermethylation of CpG islands (Figure 7).(15) (31)
Around 90% of IDH mutated gliomas harbour a single nucleotide transition (G to A) at codon 132,
resulting in an amino acid change from arginine by histidine. (15) IDH2 mutations in GBM tumours
tend to be at the arginine 172 location. (27)
IDH mutation is probably among the earliest genetic aberrations that occur during glioma
development. However, IDH mutation alone is not sufficient for tumorigenesis. (15) The proposed
mechanism by which IDH1/2 mutations contribute to the development of GBM tumours is shown in
Figure 8. Mutations in IDH-1 and IDH-2 are also common in oligodendrogliomas. (17, 32)
PTEN (also known as MMAC phosphatase) is a tumour suppressor and the PTEN gene (located on
chromosome 10q23) is frequently mutated in multiple human cancers, including prostate and breast
cancer. PTEN encodes a 403 amino acid protein with phosphatase activity and is a negative regulator
of the PI3K/Akt pathway. (33, 34)
PTEN also regulates p53 protein levels. PTEN has three phosphorylation sites located at Ser380,
Thr382, and Thr383 and these regulate stability and influence the activity of the enzyme. PTEN plays
an important role in regulating cell growth by regulating kinases, such as PI3K, and subsequently
AKT.
In mouse models, deletion of the PTEN gene in astrocytoma cell lines increased cell proliferation. In
GBM cell lines lacking PTEN, re-introduction suppressed cell proliferation. (28) PTEN is also likely to
be involved in cell migration, survival, and tumour invasion. (28)
Figure 7: Enzymatic activities of wild type and mutated IDH enzymes. (From Mondesir et al. 2016) (1)
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It is hypothesised that PTEN is either lost due to loss of heterozygosity (LOH) of chromosome 10q in
50%–70% or aberrant due to mutations in 14%–47% of primary GBM cases. LOH of chromosome 10q
is also observed in 54%–63% of secondary GBM. (28, 35) Loss of chromosome 10 is also less
common in anaplastic astrocytoma, which implies that LOH is a late step in the pathway to GBM
development. (36) LOH on chromosome 10q is associated with reduced survival and may be a useful
prognostic indicator. (35, 37)
Recent studies have shown 7% of anaplastic astrocytomas harboured PTEN mutations but they were
absent in low-grade gliomas. There is also evidence to suggest that PTEN loss does not promote
tumour growth early in GBM tumour development and is more likely to be linked to heightened
invasiveness. (35) Mouse studies have also shown that deletion of both p53 and PTEN in the CNS
results in an acute-onset high-grade malignant glioma phenotype resembling human primary GBM.
(38)
The MGMT gene is found on chromosome 10q26 and encodes the DNA repair enzyme O-6-
methylguanine-DNA methyltransferase. In tumour cells, MGMT is often silenced by binding of a
methyl group to the promoter CpG rich sites. Silencing of the gene results in a lack of expression of
the DNA repair enzyme, and therefore promotes tumour development. Approximately 40–50% of
primary GBM tumours (4, 27) and 70% of secondary GBM tumours display epigenetic MGMT
silencing. (4) MGMT silencing is also a common feature of 50% to 80% of anaplastic gliomas. (24)
Hypermethylation is not limited to MGMT; many other complex epigenetic mechanisms contribute
to the pathways that result in GBM. In tissue from a GBM tumour, hundreds, or even thousands of
genes are subject to methylation at the CpG island promoter. Indeed, hypermethylation of the CpG
island of gene promoters results in epigenetic-mediated inactivation of many genes associated with
tumour suppression (e.g. RB1), cell cycle regulation (e.g. CDKN2A), DNA repair (e.g. MGMT), tumour
invasion, and apoptosis. (24)
In a subset of GBM cases, hypomethylation or a reduction in methylation has been observed. (24)
The BRAF gene encodes the B-Raf protein, a signal transduction protein kinase that regulates the
MAPK/ERK signalling pathways and thus affects cell division, differentiation, and growth. More than
30 mutations of the BRAF gene have been identified to be associated with human cancers.
The V600E mutation of BRAF is detectable in ~50% of epithelioid GBMs. (15) Paediatric gliomas with
circumscribed growth patterns also often harbour BRAF mutations. (15)
Deletions of chromosome 1p and 19q are rare in GBM tumours, occurring in less than 10% of cases.
However, LOH or co-deletion of 1p/19q is a frequent observation in oligodendroglial tumours and is
associated with favourable treatment response to first line chemotherapy and improved survival.
(35) Losses of 1p and 19q have been observed in approximately 90% of oligodendroglial tumours,
50–70% of anaplastic oligodendroglioma, 30–50% of oligoastrocytoma and 20–30% of anaplastic
oligoastrocytoma. (4) However, the exact mechanism by which the 1p/19q co-deletion confers
tumorigenicity is yet to be fully elucidated.
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Figure 8: Emerging genetic alterations in GBM. The mutational spectrum and molecular mechanisms thought to promote tumorigenesis for IDH1 and IDH2, TERT, ATRX, H3F3A, and HIST1H3B. From Reitman et al., 2018. (39)
ALT, alternative lengthening of telomeres; ETS, E-twenty-six; GBM, glioblastoma; GABP, GA-binding protein; HR, homologous
recombination; 2HG, 2-hydroxyglutarate; H3K27me3, histone 3 lysine 27 trimethylation; H3K36me3, histone 3 lysine 36 trimethylation;
IDH, isocitrate dehydrogenase; PRC2, polycomb repressive complex 2; TERT, telomerase reverse transcriptase; TF, transcription factor.
Most GBMs upregulate the enzyme telomerase reverse transcriptase (TERT) through TERT promoter
mutations to maintain telomere length, thereby preventing senescence. (39) Activating mutations in
the TERT-promoter region are also present in >95% of oligodendroglial tumours. (15)
A subset of GBMs maintain telomere length through the alternative lengthening of telomeres (ALT)
pathway, which is associated with the helicase and histone chaperone, ATRX (α-thalassemia/mental
retardation syndrome X-linked). (39) ATRX mutations have been discovered in 85% of grade II to III
astrocytomas, in the majority of secondary GBMs, and in 30% of paediatric GBMs. (39)
The proposed mechanism by which TERT/ATRX mutations maintain telomere length in GBM tumours
is shown in Figure 8.
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Genome-wide sequencing studies have discovered mutations in histone H3 genes in GBM, including
K27M and G34R/V (Figure 8). (39) Mutated H3.3 histone disrupts epigenetic post-translational
modifications near genes involved in cancer processes and in brain function; however, the precise
role(s) of these mutations in tumorigenesis of gliomas remain unclear.
Mutations that cause inactivation of CIC (an orthologue of the Drosophila capicua gene) located on
chromosome 19q, and FUBP1 (the Far Upstream element Binding Protein 1 gene) located on
chromosome 1p, have been observed in many oligodendroglial tumours. (4)
The FUBP1 gene encodes a DNA helicase acting as a transcriptional modulator of c-myc oncogene
expression. The FUBP1 gene is mutated in 15% of oligodendrogliomas harbouring the 1p/19q co-
deletion but is absent in those without the 1p/19q deletion. Research has shown that 75% of FUBP1
mutations occurred in oligodendrogliomas already harbouring the CIC-mutation. (17, 40)
Approximately 1.2–8.3% of GBM cases carry FGFR3-TACC3 fusion proteins, which appear to promote
GBM tumour progression. (20) Fibroblast growth factor receptors (FGFR) are transmembrane kinase
proteins that are associated with numerous cancers; however, FGFR gene aberrations and FGFR
gene rearrangements are relatively rare in solid malignancies.
The FGFR3-TACC3 fusion protein has only recently been described and has a constitutively active
tyrosine kinase domain that promotes aneuploidy (aneuploidy refers to an abnormal number of
chromosomes and may contribute to the evolution of cancer). While the downstream oncogenic
signalling pathways of FGFR3-TACC3 remain unclear, a recent (2018) study suggested that FGFR3-
TACC3 may help drive mitochondrial metabolism in cancer. (41)
MicroRNAs (miRNAs) are small lengths of RNA that are 18–25 nucleotides long that are involved in
the regulation of gene expression. (24, 42) Mounting evidence suggests that miRNA levels are critical
in development of tumours. In a study of miRNAs from 480 GBM tumour samples from The Cancer
Genome Atlas dataset, high levels of miRNA-326/miRNA-130a and low levels of miRNA-323/miRNA-
329/miRNA-155/miRNA-210 were associated with improved survival. Levels of both miRNA-323 and
miRNA-329 were higher in patients with no recurrence or a longer time to progression. (35)
Angiogenesis is the process of new blood vessel formation and is a critical process in the growth of
many solid tumours, including GBMs. Tumour cells release pro-angiogenic factors including vascular
endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived epidermal
growth factor (PDGF), and SF/HGF. (43) VEGF is considered to be a key driving factor in angiogenesis
and has been identified in around 64% GBMs. (35)
Pilocytic astrocytoma is the most commonly occurring paediatric brain tumour accounting for 23.5%
of childhood CNS malignancies. (44)
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Pilocytic astrocytoma is typically characterised by genetic alterations that result in activation of
MAPK signalling. Subsets of pilocytic astrocytomas carry fusions involving different MAPK-pathway
genes, such as RAF1, PTPN11, or NTRK2. (15) As mutations in non-MAPK-pathway genes are usually
absent, pilocytic astrocytoma can be described as a ‘single-pathway disease’. (15)
Approximately 20–30% of pilocytic astrocytoma tumours (45) harbour neurofibromatosis 1 (NF1)
mutations. The NF1 gene is found on chromosome 17q11.2 and encodes neurofibromin, a protein
with an active region homologous to the catalytic domain GTPase-activating protein. (46)
For grade I pilocytic astrocytoma, BRAF duplication or mutation and gains on chromosomes 5 and 7
are commonly observed. In sporadic pilocytic astrocytoma tumours, analysis has shown that 53%–
88% of cases have focal chromosomal gains on chromosome 7q34. The mutations are often caused
by a tandem duplication that causes fusion of BRAF with the KIAA1549 gene and activation of the
BRAF gene. (44)
Ependymomas may originate from ependymal cells (which line the ventricles of the brain and the
centre of the spinal cord) or from radial glial cells (cells related to early development of the brain).
These are relatively rare tumours.
Subependymomas are benign tumours of the CNS that usually occur in the ventricular spaces,
usually the fourth or lateral ventricles. Their true incidence is unknown as they are often
asymptomatic but studies have estimated subependymomas make up 0.2–0.7% of all intracranial
tumours. (47)
There are nine distinct biological subgroups of ependymomas based on both histological and
molecular features, three in each anatomical compartment of the CNS (spine, posterior fossa, and
supratentorial). (48) Two supratentorial subgroups are classified by gene fusions involving RELA and
YAP1, while intramedullary ependymomas frequently have NF2 mutations (a gene that produces a
protein that regulates cell-to-cell contact and motility), and myxopapillary ependymomas of the
filum terminale often show multiple chromosomal aberrations. (48)
C11orf95-RELA fusions result from chromothripsis involving chromosome 11q13.1. C11orf95-RELA
fusion proteins translocate spontaneously to the nucleus, and activate members of the nuclear
factor (NF)-κB family of transcriptional regulators. The NF-κB family of transcriptional regulators are
central mediators of the cellular inflammatory response and rapidly transform neural stem cells to
form tumours. (49)
Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive tumour that primarily affects children.
DIPG arises in the glial tissue of the lowest, stem-like part of the brain, which controls many of the
body’s most vital functions. (50)
Around 27–40% of DIPG samples exhibit overexpression of EGFR; studies have shown increased
EGFR expression in correlation with increasing tumour grade. Chromosome 7 polysomy has also
been reported in 25% of DIPG samples. Amplification of the PDGFR gene in 36% of samples and the
PARP-1 gene in 27% has also been observed in other studies. PTEN loss was also a common
observation in DIPG samples. (51)
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More than >70% of DIPG in children are H3-K27M-mutant diffuse midline gliomas (see below). (15)
H3-K27M-mutant diffuse midline glioma is a WHO grade IV glioma typically located in the thalamus,
brain stem, or spinal cord. The K27M mutation in the histone-H3-encoding genes H3F3A or
HIST1H3B/C13 leads to global reduction of cellular histone H3 lysine 27 (H3-K27) trimethylation. (15)
H3-K27M-mutant gliomas frequently harbour mutations in TP53 and/or PPM1D (encoding
magnesium-dependent protein phosphatase 1D); amplification of proto-oncogenes, such as
PDGFRA, MYC, MYCN, CDK4, CDK6, or CCND1-3 (encoding cyclins D1–3), ID2, and MET is also
common. (15)
Medulloblastomas are located in the cerebellum and are fast-growing, high-grade tumours that
frequently spread to other parts of the CNS. Medulloblastomas account for 12–25% of all childhood
CNS tumours and are rare in adults. (52-56)
There is a large body of research devoted to understanding the molecular biology of
medulloblastoma: disruption of embryogenesis pathways involved in cellular proliferation and
differentiation, chromosomal amplifications and deletions, and association with viral infection (such
as the JC virus and human cytomegalovirus) have all been implicated in its pathogenesis. (57) TP53 is
dysfunctional almost 40% of medulloblastoma tumours. (58) The most common chromosomal
aberration is loss of 17p, which is observed in around 50% of medulloblastomas. Gains of 17q and 7q
copies are also frequently observed. (59) In addition, gene deletions in pathways involving cell
signalling, including Sonic Hedgehog (Shh), Wnt, Notch and Myc, are often observed in
medulloblastomas. (52)
There are currently four known distinct molecular subtypes of medulloblastoma (Wnt, Shh, group 3,
and group 4), each with different origins and pathogenesis, as reviewed by Kumar in 2017 (58). Up to
40% of medulloblastomas also show c-Myc overexpression, which is a negative prognostic factor in
group 3 and group 4 subtypes. (58, 59)
Anaplastic or malignant meningiomas (Grade III) and papillary meningiomas are malignant and tend
to invade adjacent brain tissue. Around 40–80% of meningiomas exhibit loss of chromosome 22q12
a region that encodes the NF2 gene. NF2 produces the Merlin protein, which is thought to regulate
of cell-to-cell contact and motility. Around 50% of sporadic meningiomas show mutations of the NF2
gene. (60)
Additional copies of the PDGFR and EGFR genes are also frequently observed in meningiomas. In 5–
15% of patients, multiple meningiomas occur and people with neurofibromatosis type 2 are at
increased risk. There is also evidence that previous radiation to the head or a history of breast
cancer may increase a person’s risk of meningioma. (60)
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Progression of meningiomas is associated with many alterations at the molecular level such as loss
of tumour suppressor genes and hypermethylation of CpG islands. Progesterone, androgen and
oestrogen receptors are a commonly observed feature of meningiomas. (60)
SMARCB1 mutation may play a role in tumour initiation for multiple meningiomas in familial cases
and recently a new susceptibility locus for meningioma has been identified at chromosome 10p12,
an area that encodes the MLLT10 gene. (61)
More recently, the Wnt signalling pathway has been implicated in meningioma formation and
progression, as reviewed by Pećina-Šlaus et al., 2016. (62)
A detailed understanding of the molecular biology of CNS tumours not only provides insight for new
treatments and targeted therapies directed at the exact tumour type, but it is also useful for the
detection, diagnosis, and prognosis of these cancers.
68
Clinical Practice Guidelines in Australia for the diagnosis and management of gliomas
require updating (last published in 2009). The National Institute for Health and Care
Excellence in the UK has recently published a new Clinical Guideline for Brain tumours
(primary) and brain metastases in adults.(63)
Common symptoms in patients presenting with a primary brain tumour include: headache,
nausea/vomiting, cognition changes, personality changes, gait imbalance, urinary
incontinence, hemiparesis, aphasia, hemi-neglect, visual field defect, and seizures. However,
a 2015 systematic review of the symptomatic diagnosis of cancer of the brain and CNS in
the primary care setting confirmed the symptoms of brain tumours (such as headache and
gait imbalance) are individually low risk, except for new-onset epilepsy.
While histological classification has served as the ‘gold standard’ for glioma diagnostics for
many decades, recent advances in the genomic and proteomic profiling of brain tumours
means that molecular markers (e.g., MGMT, EGFR, IDH, 1p19q, ATRX, TERT, FGFR-TACC, and
BRAF) are now being used to diagnose CNS tumours.
In May 2016, the World Health Organization (WHO) published an official restructuring of
diffuse gliomas, medulloblastomas, and other embryonal tumours; new entities are defined
by both histology and molecular features (e.g. IDH-wildtype or IDH-mutant glioblastoma and
RELA fusion–positive ependymoma).
The diagnostic biomarkers used in the 2016 WHO classification of gliomas include: IDH1/2
mutations, 1p/19q co-deletion, H3F3A or HIST1H3B/C K27M (H3-K27M) mutations, and
C11orf95–RELA fusions. Other diagnostically relevant biomarkers include: loss of nuclear
ATRX expression, TERT-promoter mutations, KIAA1549–BRAF fusions, the BRAF-V600E
mutation, and the H3F3A-G34 mutation.
Novel approaches to the genetic characterization of gliomas have been investigated,
including large-scale DNA-methylation profiling and next-generation sequencing; a DNA
methylation-based classification system for CNS tumours was reported in 2018.
In terms of prognosis, the strongest consistent predictors of survival are the age of the
patient and the preoperative Karnofsky Performance Status (KPS) score (a score assigned by
a clinician based on observations of a patient's ability to perform common tasks relating to
activity, work, and self-care).
A number of prognostic biomarkers for gliomas have been identified (such as CDK4, EGRF,
MGMT promoter methylation, TERT promoter mutations, and VEGF expression), but their
utility requires further investigation; recent studies show that combining these biomarkers
with clinical risk factors, such as age, can greatly improve their prognostic performance.
The presenting symptoms of gliomas are determined by several factors including the tumour’s size,
location and rate of growth. Common symptoms in patients presenting with a primary brain tumour
include: headache, nausea/vomiting, cognition changes, personality changes, gait imbalance, urinary
incontinence, hemiparesis, aphasia, hemi-neglect, visual field defect, and seizures. (7, 64)
68
Headaches are relatively frequent, presenting in about 50% of patients at diagnosis, but usually with
a non-specific pain pattern; progressive severity, unilateral localisation, and new-onset headache in
a patient older than 50 years are some of the features that may distinguish a tumour-associated
headache from a benign headache.
Cognitive difficulties and personality changes may develop and are often mistaken for psychiatric
disorders or dementia, particularly in elderly individuals. Gait imbalance and incontinence may be
present, usually in larger tumours with significant mass effect. Focal signs such as hemiparesis,
sensory loss, or visual field disturbances are common and reflect tumour location. Occasionally, the
development of symptoms is rapid, mimicking a stroke. Language difficulties may be mistaken for
confusion or delirium. Seizures are the presenting manifestation in about 20% to 40% of patients,
and usually a focal onset is reported. (7)
A case-controlled study examined the issue of patients presenting in the primary care setting who
were subsequently diagnosed with brain cancer. The study demonstrated that the predictive value
of any given symptom, or multiple symptoms, commonly associated with brain tumours is very low.
New-onset seizures, had the stingiest predictive value of 1.2%, meaning over 98% of patients with
new-onset seizures did not have an underlying brain tumour. And the likelihood of a brain tumour
being the underlying cause of headaches is less than one in one thousand. (65, 66)
A 2015 systematic review of the symptomatic diagnosis of cancer of the brain and CNS in the
primary care setting (which included six studies involving 159, 938 patients) confirmed that: ‘All the
symptoms of brain tumours are individually low risk, apart from new-onset epilepsy.’ (67) Seizures
were the symptom with the highest risk in adults and teenagers, but these risks were still small
(highest estimate was 2.3% in adults aged 60–69 years and below 1 in 1000 for children, teenagers
or young adults). More common features (e.g. headache) had much lower risks of CNS cancer. (67)
Many different guidelines relating to the diagnosis of brain cancer have been published worldwide
reflecting differences in healthcare systems, preferences and available options. The Australian
guidelines were published in 2009 and the Cancer Council of Australia acknowledges that they may
no longer reflect current evidence or best practice. An overview of guidelines from around the world
is presented here to reflect a broad overview of current thinking and approaches.
The current Australian clinical practice guidelines for the management of adult gliomas:
astrocytomas and oligodendrogliomas (64) (published in 2009 by the Clinical Oncological Society of
Australia and Cancer Council Australia) make the following key points regarding diagnosis:
A patient with new onset or recurrent headache uncharacteristic for that patient should
also be imaged, particularly if there are focal neurological symptoms and signs
Patients presenting with a first seizure should have adequate neuro-imaging with MRI
All patients who present with focal neurological symptoms (such as hemiparesis,
dysphasia, dysarthria, neglect, hemianopia, dressing apraxia) require neuro-imaging to
establish the cause of these symptoms.
68
However, the Cancer Council of Australia acknowledges that as ‘this resource was developed,
reviewed or revised more than five years ago. It may no longer reflect current evidence or best
practice.’ (64)
The European Society for Medical Oncology (ESMO) released clinical practice guidelines on High-
Grade Malignant Glioma, which were published in 2014. (68) Regarding diagnosis, they state that:
Tissue diagnosis is mandatory, and usually obtained by stereotactic biopsy or after tumour
resection.
Molecular markers are useful additional tools for diagnosis and treatment guidance and are
of increasing importance in daily practice.
Adequate tissue collection and preservation (e.g. sufficient material, fresh frozen tumour
tissue) should be planned prospectively. (68)
The more recent 2017 Spanish SEOM clinical guideline for diagnosis and management of low-grade
glioma recommends an algorithm approach to diagnosis.(69) The authors note that: “Recent studies
have challenged the prognostic value of WHO grading by demonstrating similar overall survival (OS)
of patients with IDH-mutant WHO grade II and WHO grade III gliomas. For the time being, the WHO
classification of 2016 recommends retaining traditional histologic grading of diffuse gliomas. Future
studies need to clarify whether grading should be modified by molecular testing.” (69)
The European Association for Neuro-Oncology (EANO) has produced a recent clinical guideline for adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is also based on the 2016 WHO classification of tumours of the central nervous system and gives a recommended pathway for different WHO grade tumours (
31
Figure 9).(70)
32
Figure 9. EANO guideline Clinical pathway for glioma - maximum safe resection is recommended whenever feasible in all patients with newly diagnosed gliomas. (70)
33
34
The American Association of Neuroscience Nurses clinical practice guidelines on the Care of the adult patient with a brain tumour (71) were published in
2014 and state that: ‘After neurological examination, the initial diagnosis is most reliably and efficiently made by radiological imaging’.
The following techniques and methods are highlighted in the American guidelines (71) for the diagnosis of brain tumours:
A. Imaging techniques
1. Head computed tomography (CT) scan with contrast
2. MRI with and without contrast
3. Magnetic resonance spectroscopy
4. Positive emission tomography (PET).
B. Systemic studies
1. CT scans of the chest, abdomen, and pelvis may be used to identify primary lesions that may have metastasized to the brain.
C. Cerebral angiography
1. Can identify the vascularity of the tumour to assist with surgical planning.
2. Preoperative embolization may be useful for vascular lesions.
D. Endocrine battery/diagnostic workup
1. Indicated for tumours located in and around the sellar region to evaluate function of the hypothalamic pituitary axis.
2. Common laboratory studies include adrenocorticotropic hormone (ACTH) and cortisol, prolactin, growth hormone, insulin-like growth factor-1,
thyroid studies (T3, T4, thyroid stimulating hormone [TSH]), testosterone, follicular stimulating hormone, and luteinizing hormone.
E. Visual tests
1. Visual field: Visual pathways encompass multiple pathways in the brain; therefore, visual field defects can help to localize tumours.
2. Fundoscopic examination can document evidence of papilledema (swelling of the optic disk), which is indicative of increased ICP (intracranial
pressure).
F. Audiometric studies
1. Audiometric studies are indicated in patients with hearing loss to document baseline hearing deficits or in patients with lesions in and around the
acoustic nerve. (71)
35
The National Institute for Health and Care Excellence (NICE) has developed a clinical guideline for Brain tumours (primary) and brain metastases in adults,
which has recently been published.(63)
The NICE guidelines outline the following evidence-based management options for brain tumours (primary) for people with newly diagnosed grade IV
glioma (glioblastoma) (Figure 10).
Figure 10. Summary of NICE guidelines for management options for people with newly diagnosed Grade IV glioblastoma. [Note: KPS = Karnofsky performance status; age is approximately 70 years; for people not covered by these options other suggestions are included in the guideline.](63)
The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas have also published recommendations for diagnostic and
therapeutic procedures with general recommendations for different tumour grades summarised in (Figure 11).
Newly Diagnosed Grade IV
Glioblastoma
KPS ≥70
Age < 70 years
Maximal safe resection or biopsy
if resection not possible
Offer
Radiotherapy 60 Gy in 30 fractions
with concomitant TMZ
and up to 6 cycles of adjuvant TMZ
Age > 70 years
MGMT positive
Offer
Radiotherapy 40 Gy in 15 fractions
with concomitant TMZ
and up to 12 cycles of adjuvant TMZ
Age > 70 years
MGMT negative
Consider
Radiotherapy 40 Gy in 15 fractions
with concomitant TMZ
and up to 12 cycles of adjuvant TMZ
KPS < 70
Age > 70 years
Any MGMT status
Consider
Best supportive care alone
36
Figure 11. Conclusions, recommendations and levels of evidence from the CGCG. (72)
Level of evidence
Grade of recommendation
General recommendations ▪ Gliomas are diagnosed using morphological criteria according to WHO classification. ▪ Karnofsky performance score, neurological function, and age need to be considered in
clinical decision making in neuro-oncology. ▪ Magnetic resonance imaging (MRI) can be used to detect the presence of tumour and
guide managements such as biopsy, surgery and radiation. ▪ Maximal safe resection is the first option for all gliomas, while minimizing the
postoperative morbidity. ▪ When surgery is not feasible, a biopsy should be performed to obtain a histological
diagnosis. ▪ MGMT promoter methylation, IDH mutations and 1p/19q co-deletion are commonly
determined depending on the histological and clinical contexts.
1a 1b 2b 2a 4 1b
A A B B C A
Low grade gliomas (WHO grade II) ▪ Younger patients (≤40 years of age) with gross total resection can be observed after
surgery, but close follow-up is needed. ▪ For patients with high risk (age >40 years or none receiving gross total resection), an
adjuvant treatment is indicated at any time. ▪ Radiotherapy may be selected for high risk patients (age >40 years or gross total
resection not received). ▪ Chemotherapy is an option as initial treatment for patients with large residual tumours
after surgery or unresectable tumours, especially when 1p/19q loss is present.
1b 1b 1b 1b
B B A B
Anaplastic gliomas (WHO grade III) ▪ Patients with 1p/19q co-deleted anaplastic oligodendroglioma (oligoastrocytoma)
should receive chemotherapy with alkylating agents with or without radiotherapy. ▪ MGMT promotor methylation could be a predictive marker for response to alkylating
chemotherapy in IDH wild-type anaplastic gliomas. ▪ Temozolomide chemotherapy is standard treatment at progression after surgery and
radiotherapy.
1b 2b
B B
37
1b
A
Glioblastoma (WHO grade IV) ▪ Radiotherapy combined with temozolomide remains the standard of care for newly
diagnosed glioblastoma. ▪ In elderly patients (>65 years) with IDH wild-type and MGMT promoter methylation,
temozolomide chemotherapy may be considered, while radiotherapy is the treatment of choice for patients with an unmethylated gene promoter.
▪ Bevacizumab (± irinotecan) is an option for the management of recurrent glioblastoma.
1b 1b 1b
A B B
While histological classification has served as the ‘gold standard’ for glioma diagnostics for many decades, it is associated with considerable inter-observer
variability. Due to recent advances in the genomic and proteomic profiling of brain tumours, molecular markers (e.g., MGMT, EGFR, IDH, 1p19q, ATRX,
TERT, FGFR-TACC, and BRAF) are now being used to diagnose CNS tumours. (73)
It is now recommended that an ‘integrated diagnosis’ incorporating all tissue-based information be given for each patient, which combines histological
classification (e.g., diffuse glioma), WHO grade (i.e., the degree of tumour malignancy, from Grade I to IV), and molecular information (e.g., IDH mutant).
(49)
The main molecular markers used in the diagnosis of CNS tumours are shown in Table 2. Some other molecular markers associated with glioma (and their
method of detection) is summarised in Table 3.
Table 2: Main molecular markers used in the diagnosis of CNS Tumours. From Gupta and Dwivedi, 2017. (49)
Tumours Molecular marker
Astrocytoma IDH1/2, TP53, ATRX
Oligodendroglioma IDH1/2, 1p/19q co-deletion, TERT
Glioblastoma IDH1/2, TERT, MGMT methylation
Diffuse midline glioma, H3 K27M-mutant H3 K27M, ATRX, TP53
38
39
Table 3: Other molecular markers associated with glioma. From Ludwig & Kornblum, 2017. (74)
40
41
The idea of an integrated diagnosis led to the updated 2016 WHO classification system for CNS tumours. (5) The differences between the 2016 and 2007
CNS tumour classifications are reviewed by Gupta et al., 2017. (49) In brief, a few entities have been added (e.g. diffuse midline glioma, H3 K27M-mutant,
RELA fusion-positive ependymoma, embryonal tumour with multilayered rosettes, C19MC-altered, and hybrid nerve sheath tumours), and a few variants
have been deleted (e.g. glioblastoma cerebri, protoplasmic and fibrillary astrocytoma, and cellular ependymoma). (49)
The current WHO grading system used for CNS tumours is as follows:
• Grade I: Tumours do not meet any of the criteria. These tumours are slow growing, non-malignant, and associated with long-term survival;
• Grade II: Tumours meet only one criterion, i.e., only cytological atypia. These tumours are slow growing but recur as higher-grade tumours. They
can be malignant or non-malignant;
• Grade III: Tumours meet two criteria, i.e., anaplasia and mitotic activity. These tumours are malignant and often recur as higher-grade tumours;
• Grade IV: Tumours meet three or four of the criteria, i.e., showing anaplasia, mitotic activity with microvascular proliferation, and/or necrosis.
These tumours reproduce rapidly and are very aggressive malignant tumours. (49)
Grading of selected CNS tumours according to the 2016 WHO classification system of CNS tumours is shown in Table 4.
42
Table 4: Grading of selected CNS tumours according to the 2016 CNS WHO. From Louis et al., 2016.
Over the past three decades, there has been a change from invasive techniques which often demonstrated tumours by indirect means, to advanced cross-
sectional imaging modalities which now directly illustrate these lesions. Computed tomography (CT) and magnetic resonance imaging (MRI) currently form
43
the mainstay of brain tumour imaging. MRI has largely replaced CT scanning in the management of patients with brain tumours, with CT only used in initial
imaging and in monitoring acutely changing neurological symptoms.
MRI has the benefit of being more specific and sensitive than CT, particularly in the context of evaluating non-enhancing lesions. MRI can also generate
images in three planes (axial, coronal and saggital), whereas CT generates images only in the axial plane. MRI imaging modalities including MR
spectroscopy, perfusion imaging and diffusion scanning; all of which are beneficial in differential diagnosis of other high grade gliomas, such as, anaplastic
astrocytoma and anaplastic ependymoma, primary CNS lymphoma, metastatic tumours, brain abscess and other neurologic processes. (75, 76)
Nevertheless, while both imaging techniques reveal morphological information, they are limited in their potential to assess specific and reproducible
information about biology and activity of the tumour.
More recently, the use of molecular imaging with Positron Emission Tomography (PET) has been investigated in neuro-oncology. The advantage provided by
PET is the ability to provide additional metabolic information of the tumour, for patient management as well as for evaluation of newly developed
therapeutics. (77)
The use of PET with radiolabelled glucose and amino acid analogues aids in the diagnosis of tumours, differentiates between recurrent tumours and
radiation necrosis, and guides biopsy or treatment. 11C-methionine (MET) is the most popular amino acid tracer used in PET imaging of brain tumours.
Because of its characteristics, MET PET provides a high detection rate of brain tumours and good lesion delineation. (78) The emergence of new fluorinated
amino acid tracers such as [18F]Fluoroethyl-l-tyrosine (FET) will likely increase the availability and utility of PET for patients with primary brain tumours. PET
can characterise brain tumours by investigating other metabolic processes such as DNA synthesis or thymidine kinase activity, phospholipid membrane
biosynthesis, hypoxia, receptor binding and oxygen metabolism and blood flow, which will be important in the future assessment of targeted therapy. (79)
Diffusion-weighted imaging (DWI) also has significant value in the assessment of brain tumours, as reviewed by Villanueva-Meyer et al., 2017. (80)
Note: there is an inherent problem with constructing evidence-based guidelines in radiology, in part because of the rapidly evolving technology in CT, MRI,
PET, and also nuclear medicine techniques. (64)
The genetic characterisation of gliomas based on next-generation sequencing (NGS) or large-scale DNA-methylation profiles may facilitate integrated
histological and molecular glioma classification.
44
A glioma-tailored gene panel has been developed using NGS for the molecular diagnosis of gliomas, which covers 660 amplicons derived from 20 genes
frequently aberrant in different glioma types. (81) The NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular
classification into distinct biological groups, including:
IDH1/IDH2 mutant astrocytic gliomas with frequent ATRX and TP53 gene mutations
IDH mutant oligodendroglial tumours with 1p/19q co-deletion, TERT promoter mutation and frequent CIC gene mutation
IDH wildtype GBMs with frequent TERT promoter mutation, PTEN mutation and/or EGFR amplification.
DNA-methylation profiling for the DNA methylation-based classification of CNS tumours may also improve diagnostic accuracy in a routine setting, as
recently reported by Capper et al., 2018. (82)
It has been observed that in GBM tumours, a higher number of genetic aberrations tend to be linked to shorter survival time. (14) There is typically a high
level of chromosomal instability in GBM tumours and structural abnormalities and changes in the number of chromosomes are common.
When considering the prognosis of a patient with GBM a number of factors need to be taken into account (Figure 12). (83) A review by Chaudhry et al.,
2013 (83) found that the strongest consistent predictors of survival are the age of the patient and the preoperative Karnofsky Performance Status (KPS)
score, which is a score (between 10 and 100) assigned by a clinician based on observations of a patient's ability to perform common tasks relating to
activity, work, and self-care.
Figure 12: Positive and negative predictors of long-term survival in patients with glioblastoma (GBM). From Chaudhry et al., 2013. (83)
45
Biomarkers may also provide information about prognosis. (35, 84) Some of the potential biomarkers for gliomas are shown in Table 5; those specific for GBM are shown in
► Age < 65 years
► KPS > 70
► Gross total resection
► Combined radiotherapy & chemotherapy
► Re-operation
► High Ki67 (an indicator increased cell proliferation)
► Location (paraventricular & crossing midline)
► No combined radiotherapy & chemotherapy
► Postoperative complications
46
Table 6, and those for high-grade glioma are shown in
Table 7.
There have been varied findings relating to MGMT promoter methylation and prognosis. A 2016
meta-analysis of the prognostic value of the status MGMT promoter methylation measured by a
pyrosequencing assay in GBM patients found that positive MGMT promoter status was related to
increased survival. (85) This was confirmed in a more recent meta-analysis using data from 34
studies which concluded that in GBM patients MGMT methylation was associated with longer overall
survival, but not longer progression-free survival.(86) This was confirmed in another 2018 meta-
analysis of 10 eligible studies which demonstrated that MGMT promoter methylation was not
significantly associated with better progression-free survival (pooled HRs, 0.653; 95% CI: 0.414–
1.030; p = 0.067). (86)
In anaplastic gliomas, MGMT methylation is a marker of more favourable prognosis, irrespective of
the treatment course chosen. (24)
Survival is also improved for patients with IDH-mutation positive tumours. Indeed, another study
showed a combination of IDH1 mutations and MGMT methylation status predicts survival in GBM
tumours more accurately than either one of the markers alone. (87)
Other potential biomarkers include amplification of CDK4 and EGRF (and deletion of CDKN2A) and
TERT promoter mutations, which predict poor prognosis in GBM. The ATRX mutation also carries a
favourable prognostic implication in anaplastic gliomas, but is mostly restricted to IDH-mutant
tumours that are largely G-CIMP positive. Finally, a correlation between VEGF expression and
survival time has been reported suggesting that VEGF may also be a useful potential prognostic
marker. (35)
47
Table 5: Molecular biomarkers and their clinical relevance in gliomas. From Siegal, 2015. (88)
48
Table 6: Molecular and metabolic alterations in GBM and their potential biomarker status. From McNamara et al., 2013. (35)
Table 7: Prognostic/predictive molecular markers in high-grade gliomas. From Masui et al., 2012. (4)
MGMT methylation IDH1/2 mutation
1p/19q codeletion EGFR & P13K pathway* P53 pathway mutation
Rb pathway mutation
Anaplastic glioma (Grade III)
Prognostic (AA, AO, AOA)
Prognostic (AA, AO)
Prognostic/predictive (AO)
Negatively prognostic (AA)
Marginal Marginal
Glioblastoma (Grade IV)
Prognostic/predictive Prognostic Prognostic? Negatively prognostic/predictive?
Marginal Marginal
*factors that may assist with prediction of aggressive nature of gliomas
AA, analplastic astrocytoma; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma.
A microRNA (miRNA) is a small non-coding ribonucleic acid (RNA) molecule that contains about 22
nucleotides. Up- or downregulation of miRNAs is involved in GBM progression; therefore, miRNAs
may represent novel biomarkers of the disease.
A study published in 2017 used The Cancer Genome Atlas to evaluate the prognostic accuracy of
potential biomarkers such as miRNAs, gene expressions, gene signatures, and methylation. (89) The
authors found that to predict overall survival at two years after diagnosis the miRNAs Mir21 and
Mir222 were useful, particularly when age was also taken into account.
They concluded that: ‘Although some biomarkers and gene signatures are statistically significantly
associated with overall survival of patients with GBM, their ability to accurately prognose cumulative
or incident overall survival events is very limited. Predicted risk scores that combine biomarkers with
49
clinical risk factors, such as age, can greatly improve the prognostic performance of these
biomarkers.’ (89)
There is evidence that cancer stem cells may play an important role in tumour development. The
presence of cancer stem cells and stem cell markers, including CD133 and nestin, in GBM tumours
has been observed; both are markers for prognosis. (90)
Recent findings show that cancer stem cells may be resistant to chemo and radiotherapy, (35) and
there is some evidence that tumours with higher populations of cancer stem cells confer decreased
overall and progression-free survival. (27) However, there is still some debate about the existence of
a true cancer stem cell in glioma and the utility of glioma stem cell detection as a prognostic
biomarker. (74)
Known mutations of gliomas, such as EGFRvIII, can be detected by analysing soluble, circulating
proteins or circulating tumour DNA (ctDNA) isolated from plasma. miRNAs can also be found in
extracellular vesicles shed by the tumour cells. However, circulating tumour cells are difficult to
detect and only a single cell type of the heterogeneous tumour composition. Alternatively,
extracellular vesicles reflect the complex heterogeneity of the whole tumour, as well as its
adaptations to therapy, and are appealing candidates for a comprehensive biomarker for gliomas.
(91)
In addition, novel aptamer substrates are being used to detect tumour cells circulating in peripheral
blood to improve early detection and/or monitoring residual disease after treatment. Aptamers are
small single-stranded nucleic acids that fold into a well-defined three-dimensional structure. They
show a high affinity and specificity for their target molecules. Research has shown that anti-EGFR
RNA aptamer substrates can specifically recognise, capture, and isolate both human and murine
GBM cells expressing wild-type EGFR and mutant EGFRvIII with high sensitivity and specificity. (92)
The potential use of aptamers in the diagnosis and treatment of GBM was reviewed by Hays et al., in
2017. (18)
In summary, the use of biomarkers in the diagnosis and prognosis of CNS tumours is on the rise.
While current evidence has found the ability of these biomarkers for predicting overall survival in
gliomas is limited, incorporating other clinical risk factors, such as age, can greatly improve the
prognostic performance. Combining genomic data and imaging data may also improve the accuracy
of the diagnosis and the prognostic performance.
50
There are currently two drugs on the PBS (Pharmaceutical Benefits Scheme) specifically
listed for the treatment of glioblastoma (a malignant tumour affecting the brain) -
Carmustine (Gliadel®) and Temozolomide (numerous brands including Astromide®,
Temodal® and APO-Temozolomide®).(93)
Standard options for treatment of gliomas include surgical resection, radiation and
chemotherapy, either alone or in combination.
Current surgical techniques for tumour resection include cortical mapping of the brain,
fluorescence-guided surgery, laser interstitial thermal therapy, and intraoperative mass
spectrometry.
The current standard of care for the medical management of newly diagnosed glioblastoma
following resection includes the addition of temozolomide to radiation therapy. However,
most tumours eventually develop resistance to temozolomide (TMZ) and there is no
standard chemotherapy for recurrent or progressive glioblastoma because of unfavourable
outcomes with currently available cytotoxic therapies.
Until recently, whole brain radiation therapy (WBRT) was the treatment of choice for brain
cancer. Now, use of stereotactic radiosurgery (SRS) is becoming more common in selected
patients. SRS relies on image-guidance to precisely deliver radiation at a higher dose,
thereby reducing treatment time and toxicity.
In October 2015, the use of tumour-treating fields (TTFields or OptuneTM)—which delivers
low-intensity, intermediate-frequency, alternating electric fields via a specialized helmet
worn to inhibit tumour growth—in combination with temozolomide for the treatment of
adults with newly diagnosed glioblastoma was approved by the US Food and Drug
Administration (FDA). TTFields is also now FDA-approved for treatment of recurrent
glioblastoma as a monotherapy after surgical and radiation options have been exhausted.
Tumour-treating fields (TTFields or OptuneTM) has been called a “fourth cancer treatment
modality,” after surgery, radiotherapy, and pharmacotherapy.
The molecular classification of each individual tumour is increasingly being used to drive
therapeutic decisions in the treatment of gliomas, and novel targeted therapies are under
development. However, due to the complexity of glioblastoma, a combination of molecular
therapies will likely be necessary. Predictive DNA sequencing followed by targeted therapy
will support the implementation of precision medicine in neuro-oncology.
Immunotherapies such as peptide vaccines, dendritic cell vaccines, and immune checkpoint
inhibitors (anti-PD-1 and anti-CTLA-4) have demonstrated improved overall survival for
patients with glioblastoma in clinical phase II/III trials. Currently, at least three
immunotherapies are in phase III clinical trials.
Only modest benefit has been observed with the currently available salvage therapies for
patients with recurrent glioblastoma, which include re-resection, re-irradiation, and systemic
therapies.
Emerging therapeutic strategies (including gene therapy, oncolytic virotherapy,
nanoparticles, stem cell therapy, and blood–brain barrier disruption) are also showing
promising results in the treatment of glioblastoma.
51
The approaches to treatment for glioma are based on the histological finding, grade of the tumour
and age and medical condition of the patient. Standard options for treatment include surgical
resection, radiation and chemotherapy, either alone or in combination. (94)
The current standard of care for the medical management of newly diagnosed glioblastoma (GBM),
following resection, includes the addition of temozolomide (TMZ) to radiation therapy (RT), which
was found in a 2005 clinical trial to significantly prolong survival. (95) However, the benefit of TMZ is
fairly modest, with a median overall survival 12.1 months for RT alone compared to 14.6 months for
RT combined with TMZ. (43, 95)
Recently, advances in knowledge regarding the molecular biology of gliomas and how it relates to
treatment response has led to new therapeutic approaches and opportunities for personalised
treatment regimes. (94) Here we provide an overview of the standard options of treatment for brain
cancers, and highlight some of the emerging therapeutic strategies.
Surgery is an important modality for improving prognosis in patients with gliomas. (96) A
retrospective systematic meta-analysis (performed on over 41,000 newly diagnosed GBM patients)
found gross total resection (GTR) was superior to subtotal resection (STR), with a 61% increase in
likelihood of a one-year survival and a 51% likelihood of a 12-month progression free survival. (97)
As stated in a recent review by Lara-Valazquez et al., 2017: ‘Techniques such as cortical mapping of
the brain, fluorescence-guided surgery, laser interstitial thermal therapy and intraoperative mass
spectrometry are used nowadays in the operating room for tumour resection. In the near future,
evolving technologies such as an optical coherence tomography (for further information see
Treatment: Image guided surgery section) will revolutionize the surgical field of central nervous
system (CNS) gliomas, allowing real-time tumour delineation in a short period of time.’ (96)
The current Australian Clinical Practice Guidelines (98) for the management of adult gliomas:
astrocytomas and oligodendrogliomas recommend the following surgical management for different
grades of glioma.
There is definitely a role for attempted resection of a LGA. It should probably be done at the
time of diagnosis for the following potential benefits: more accurate diagnosis, palliation of
symptoms, extension of survival, reduced chance of malignant transformation and possible
cure.
Recommendation of resection should be tempered if the tumour is diffuse, located in an
eloquent area or less than 10 cm3 in volume.
Standard microsurgical techniques should be employed with the addition of stereotactic
guidance if available.
Awake surgery or cortical mapping are optional but may reduce the incidence of
postoperative neurological deficit if the aim of surgery is to palliate and secure a diagnosis
rather than prolong life or achieve a cure.
52
A tissue diagnosis should be obtained in all patients with suspected HGA before commencing
definitive treatment.
Anti-neoplastic treatment should not be offered without a tissue diagnosis unless biopsy is
considered too dangerous.
Patients with HGA should have surgery for tumour resection if safe as this extends survival
when compared to biopsy alone.
Patients with HGA should have surgery for maximal tumour resection, aiming for gross
macroscopic resection if safe, as this extends survival when compared to biopsy, subtotal or
partial resection.
Patients with HGA who are over the age of 65 or have poor performance status should have
surgery for tumour resection if they are fit for surgery, as this extends survival when
compared to biopsy alone.
Patients with HGA benefit from implantation of carmustine wafers at the time of surgical
resection of tumour as they provide a modest survival benefit of 8 to 11 weeks.
Patients with recurrent HGA, particularly younger, asymptomatic patients, may benefit from
resection of tumour.
Surgery for patients with HGA should be conducted in accredited facilities complying with all
relevant State, Federal, professional and educational policies, standards and guidelines.
Surgery for patients with HGA should be conducted in a multidisciplinary environment with
input from neuroradiology, intensive care, medical and radiation oncology, neuropathology,
neurology, specialist surgery and nursing and allied health services.
Surgery for patients with HGA should be conducted in a facility where an operating
microscope, ultrasonic surgical aspirator and cortical mapping equipment are available.
Intra-operative frameless neuronavigation improves extent of resection and survival of
patients with HGA compared to unguided microsurgery, and its use is recommended.
All patients with suspected OG or OA should undergo a biopsy for histological confirmation
of tumour type and grade and to permit molecular analysis.
Maximal gross surgical resection is recommended where technically feasible, as this has
been shown to increase survival.
All suspected OGs or OAs must undergo histological confirmation as radiological features
alone are inadequate for diagnosis and staging.
Observation only may be an acceptable strategy in grade II tumours with good prognostic
features.
For childhood gliomas a consensus statement on surgical approaches has been developed and for
hypothalamic chiasmatic glioma (HCLGG) primary surgical resection was not recommended. For
DIPG, biopsy was recommended to ascertain biological characteristics to enhance understanding and
targeting of treatments, especially in clinical trials. For high-grade glioma (HGG), biopsy is
recommended.(99)
53
A 2013 Cochrane review examining biopsy versus resection for low-grade glioma (LGG) was unable
to draw conclusions due to a lack of suitable studies. (100) An updated version in 2017 (101)
identified no new studies for inclusion, and the authors concluded that: ‘Currently there are no
randomized clinical trials or controlled clinical trials available on which to base clinical decisions.
Therefore, physicians must approach each case individually and weigh the risks and benefits of each
intervention until further evidence is available. Future research could focus on randomized clinical
trials to determine outcomes benefits for biopsy versus resection.’
Another Cochrane review, updated in 2011, examining biopsy versus resection for high-grade glioma
(HGG) concluded: ‘There is no high quality evidence on biopsy versus resection for HGG that can be
used to guide management. The single included RCT is of inadequate methodology to reach reliable
conclusions. Further large multi-centred RCTs are required to conclusively answer the question of
whether biopsy or resection is the best initial surgical management for HGG.’ (102)
The 2014 ESMO Clinical Practice Guidelines for high-grade glioma state: ‘it may be beneficial to
attempt maximal tumour resection provided that neurological function is not compromised by the
extent of resection [II, C]’. Although ‘when microsurgical resection is not safely feasible (e.g. due to
location of the tumour or impaired clinical condition of the patient), a biopsy should be carried out.’
(68)
A 2014 Cochrane review (103) examined the benefits of image-guided surgery for the resection of
brain tumours. Four relevant randomised clinical trials were identified using four different
techniques: intra-operative MRI (iMRI; to assess the amount of remaining tumour), 5-aminolevulinic
acid (5-ALA) fluorescence guided surgery (to mark out the tumour), neuronavigation and diffusion
tensor imaging (DTI)-neuronavigation. The authors concluded that: ‘There is low to very low quality
evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI-
neuronavigation increases the proportion of patients with high grade glioma that have a complete
tumour resection on post-operative MRI.’ (103)
The review was updated in 2018, (104) and the authors concluded that: ‘Intra-operative imaging
technologies, specifically iMRI and 5-ALA, may be of benefit in maximising extent of resection in
participants with high grade glioma. However, this is based on low to very low quality evidence, and
is therefore very uncertain. The short- and long-term neurological effects are uncertain. Effects of
image-guided surgery on overall survival, progression-free survival, and quality of life are unclear. A
brief economic commentary found limited economic evidence for the equivocal use of iMRI compared
with conventional surgery. In terms of costs, a non-systematic review of economic studies suggested
that compared with standard surgery use of image-guided surgery has an uncertain effect on costs
and that 5-aminolevulinic acid was more costly. Further research, including studies of ultrasound-
guided surgery, is needed.’ (104)
There is evidence that more extensive surgical resection is associated with improved life expectancy
for both low-grade and high-grade glioma patients. Awake intraoperative stimulation mapping
allows surgeons to maximise the extent of tumour resection while minimising morbidity.
54
A 2017 retrospective chart review of 49 patients who underwent resection of tumours that were
located within the primary motor cortex found ‘awake motor mapping was not superior to mapping
done under general anaesthesia with regard to long-term functional outcome.’ (105)
Awake intraoperative stimulation mapping may be more particularly relevant to the resection of
gliomas present within or adjacent to language pathways. Unlike motor function, speech and
language are distributed widely across the brain. Therefore, postoperative language retention may
be improved by using language-mapping techniques in conjunction with standardised
neuroanaesthesia and neuromonitoring. (29)
Laser interstitial thermal therapy (LITT) is a newly developed method for treating brain tumours that
are hard to reach by conventional surgery. A laser catheter is implanted using advanced computer
imaging to guide placement into the tumour. The laser is then used to heat the tumour tissue to a
temperature that can destroy it. LITT is increasingly being used in the management of intracranial
tumours, although there is still a need for larger scale trials to develop standard protocols for its use
(as reviewed by Ashraf et al., 2018 (106)). LITT may help patients who do not respond to stereotactic
radiosurgery (see below) or have radiation necrosis. Indeed, LITT may be an effective alternative to
surgery as a salvage treatment in carefully selected patients with recurrent GBM. However, its role
in the treatment of newly diagnosed unresectable GBM requires further study.
OCT is a non-invasive label-free technique that provides high-quality 2D imaging in non-cancer and
cancer tissues and may represent a future strategy for glioma surgery; however, further analysis is
needed to determine whether tumour visualisation is enhanced with OCT compared to traditional
methods. (96)
Temozolomide (TMZ) is an oral alkylating agent that penetrates the blood–brain barrier (BBB). In the
body TMZ is rapidly converted MTIC, an agent that prevents cell division by interrupting normal DNA
replication. (107) Treatment of GBM with TMZ began in the USA in 1999 and since this time modest
improvements in patient GBM survival times have been observed. (108)
A 2013 Cochrane review (109) of TMZ use found three high quality clinical trials and observed that
TMZ increased survival (HR 0.84, CI 0.50 to 0.68, P < 0.001) and time to progression (HR 0.52, CI 0.42
to 0.64, P < 0.0001). There were no significant impacts on quality of life and only a low incidence of
early adverse events. Grade 3/4 haematological toxicity was observed in 5–14% of patients and
longer term adverse effects of TMZ are still unknown. (109)
For recurrent GBM only one trial was included; TMZ did not increase overall survival but it did
increase time to progression (HR 0.68, CI 0.51 to 0.90, P = 0.008). (109)
Most tumours eventually develop resistance to TMZ and there is no standard chemotherapy for
recurrent or progressive GBM because of unfavourable outcomes with currently available cytotoxic
therapies. (43) Common side effects include temporary hair loss, nausea and vomiting (may be
55
severe), loss of appetite, constipation, diarrhoea, skin rash, tiredness, weakness, dizziness, blurred
vision, insomnia, mouth sores, unpleasant taste, coughing, and headache.
Note: Silencing of MGMT enables use of TMZ. When MGMT is functioning, such agents are of limited
use as the DNA repair enzyme counteracts their functionality. TMZ acts by damaging DNA via
addition of a methyl group at the O-6 position; when MGMT is silenced in GBM, this allows tumour-
specific action. (4) TMZ induced alkylations lead to DNA damage in the tumour cells, including DNA
double strand breaks and mismatches, that in turn cause apoptosis and cytotoxicity in tumour cells.
(110)
A randomized controlled study (RTOG 9802) that studied the combined chemotherapy agents
procarbazine, CCNU, and vincristine (PCV) used in conjunction with fractionated radiotherapy (FRT)
in patients with "high-risk" WHO grade II gliomas found that this regime improved both progression-
free survival and overall survival.(111)
Wafers saturated with chemotherapy agents can be inserted directly into the cavity at the time of
resection. A 2011 Cochrane review (112) assessed two randomised controlled trials of the effect of
carmustine (Gliadel®) impregnated wafers in high-grade glioma. Survival was increased with the
wafers compared to placebo (HR 0.65, 95% CI 0.48 to 0.86, P = 0.003). For recurrent disease, no
significant survival increase was observed (HR 0.83, 95% CI 0.62 to 1.10, P = 0.2). Adverse events
were not more common with the wafers compared to placebo. (112)
A more recent meta-analysis included 60 studies of carmustine wafer use in high-grade glioma
patients. Results showed that for newly diagnosed high-grade glioma, 1-year overall survival was
67% with carmustine wafers compared to 48% without but for recurrent high-grade glioma there
was no significant difference.(113)
Due to concern regarding adverse effects (including cerebrospinal fluid leakage and intracranial
hypertension) and challenges in interpretation of imaging findings after wafer placement, the use of
such wafers has not been widely adopted. (39, 113) There has also been concern about the use of
wafers and the impact on eligibility for inclusion in other randomised controlled trials.
A 2008 Cochrane review of adjuvant treatment of anaplastic oligodendrogliomas (AO) and anaplastic
oligoastrocytomas (AOA) included two randomised controlled trials investigating surgery plus
radiotherapy (RT) plus early PCV (procarbazine, lomustine, and vincristine) chemotherapy compared
to surgery plus RT alone. No survival benefit was observed with the addition of early PCV
chemotherapy, however an increase in progression-free survival was observed following PCV
chemotherapy before surgery or after surgery and RT. (114)
To improve prognosis in recurrent GBM, the International Initiative for Accelerated Improvement of
Glioblastoma Care developed a treatment protocol based on a combination of drugs not
traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being
well-tolerated and are already marketed and used for other non-cancer indications. (115)
56
The focus was on adding drugs which met the following criteria: a) were pharmacologically well
characterised, b) had a low likelihood of adding to patient side effect burden, c) had evidence for
interfering with a recognised, well-characterised growth promoting element of GBM, and d) were
coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological
features of GBM growth.
Nine drugs meet these criteria and the authors propose a treatment protocol that adds them to
continuous low dose TMZ in patients with recurrent disease after primary treatment with the Stupp
Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, (CUSP9) are:
aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir,
and sertraline.
CUSP9 is weighted towards interference with GBM stem cell function, which offers a higher reward
yet similar risks as targeting the tumour cell population as a whole. The authors conclude that ‘over
99% of patients will experience progression post-primary treatment and the short median survival of
patients with glioblastoma warrant taking the measured and manageable risks of CUSP9’. (115)
A Phase I proof-of-concept clinical trial to assess the safety of CUSP9 combined with metronomic
TMZ in the treatment of recurrent GBM is currently recruiting participants (NCT02770378).
The molecular classification of each individual tumour to identify markers that predict response to
chemotherapeutic agents is an emerging development area in GBM treatment. (27)
For example, MGMT promoter methylation is correlated with reduced resistance to the
chemotherapy drug TMZ in GBM. Similarly, MGMT promoter methylation has been associated with
improved outcome in patients with anaplastic astrocytoma (AA) and anaplastic oligoastrocytoma
(AOA) treated with TMZ at recurrence. (4) MGMT status may also influence the decision to withhold
TMZ or the duration of TMZ treatment in the elderly, although further research is needed. (39)
Long-term follow up results from the Radiation Therapy Oncology Group 9402 and European
Organisation for Research and Treatment of Cancer 26951 trials only demonstrated an overall
survival benefit from RT plus PCV (procarbazine, lomustine, and vincristine) in patients with
anaplastic oligodendroglial tumours with the 1p/19q codeletion. (116, 117)
Therefore, routine tumour testing for 1p/19q and MGMT for GBM patients is under investigation.
(68, 116, 117)
A 2015 Cochrane review assessed the effects of early postoperative RT versus RT delayed until
tumour progression for low-grade intracranial gliomas (LGG) in people who had initial biopsy or
surgical resection. (118)
The authors concluded that: ‘There was no significant difference in overall survival between people
who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of
rescue therapy with radiation in the control arm. People who underwent early radiation had better
57
seizure control at one year than people who underwent delayed radiation. There were no cases of
radiation-induced malignant transformation of LGG. However, it remains unclear whether there are
differences in memory, executive function, cognitive function, or quality of life between the two
groups since these measures were not evaluated.’ (118)
Hypofractionated radiotherapy allows the dose to be intensified and the delivery of a higher dose
per fraction, over a shorter time frame. This has the advantages of improving the number of tumour
cells killed and slowing the rate at which the tumour grows back. (119) Hypofractionated-intensity
modulated radiotherapy (hypo-IMRT) and volumetric-modulated arc therapy (VMAT) have shown
promising results in clinical trials when used in GBM patients in combination with
chemotherapy.(120-122)
The use of stereotactic radiosurgery (SRS) is becoming more common in selected patients. SRS relies
on image-guidance to precisely deliver radiation at a higher dose, thereby reducing treatment time
and toxicity. Preservation of neurocognitive function may also be improved.
High energy beams are accurately focussed on a selected intracranial target. There are several
methods to deliver these high energy beams, including: a linear accelerator or LINAC rotating on a
gantry (X-Knife, Novalis) or manipulated with a robotic arm (CyberKnife), or cobalt sources placed
into a helmet (Gamma-Knife).
SRS has the advantage of being non-invasive and can be performed as an outpatient procedure. It is
often used in patients with recurrent GBM to avoid further surgical procedures or in addition to
conventional RT. (123)
In a small retrospective review of 18 patients with biopsy-confirmed recurring or unresectable
pilocytic astrocytoma undergoing SRS, it was found that 11 patients with tumour-related symptoms
improved after SRS. Symptomatic oedema after SRS occurred in 8 patients, which resolved with
short-term corticosteroid therapy in the majority of those without early disease progression. The
authors concluded that: ‘Radiosurgery has low permanent radiation-related morbidity and durable
local tumour control, making it a meaningful treatment option for patients with recurrent or
unresectable pilocytic astrocytoma in whom surgery and/or external beam radiotherapy has failed.’
(124)
Hypo-fractionated SRS (using up to five fractions) may also provide treatment benefits. (125) A
recent study found hypo-fractionated SRS was a safe and feasible treatment in patients with single,
large brain metastases unsuitable for surgical resection, with good brain local control and limited
toxicity. (126)
However, in a 2016 Cochrane review that assessed the effects of postoperative external beam
radiation dose escalation in adults with high grade glioma (HGG), the authors concluded that:
‘Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional
radiotherapy, particularly for individuals aged 60 and older with glioblastoma.’ In addition, there is
currently insufficient data regarding ‘hyperfractionation versus conventionally fractionated radiation
58
(without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation
(without chemotherapy)’ in the treatment of HGG.’ (127)
Combining SRS with other therapies like immunotherapies (discussed below) may improve
outcomes, although further research is required. (128)
Despite the positive results, further evidence in the form of phase III randomised trials is needed to
assess the durability of SRS for treating patients in specific clinical situations. (129)
A 2017 Cochrane review found combining SRS with WBRT does not appear to confer a survival
benefit over WBRT alone. (130) The authors concluded that: ‘Given the unclear risk of bias in the
included studies, the results of this analysis have to be interpreted with caution. In our analysis of all
included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However,
performance status and local control were significantly better in the SRS plus WBRT group.
Furthermore, significantly longer OS was reported in the combined treatment group for recursive
partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our
outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and
the risk of bias in the majority of included studies was mostly unclear.’ (130)
A 2012 Cochrane review assessed the effectiveness of WBRT given alone or in combination with
other therapies in adults with newly diagnosed multiple brain metastases. (131)
The review was updated in 2018 with the addition of 10 randomised clinical trials. (132) The authors
concluded that: ‘None of the trials with altered higher biological WBRT dose-fractionation schemes
reported benefit for overall survival (OS), neurological function improvement (NFI), or symptom
control compared with standard care. However, OS and NFI were worse for lower biological WBRT
dose-fractionation schemes than for standard dose schedules. The addition of WBRT to radiosurgery
improved local and distant brain control in selected people with brain metastases, but data show
worse neurocognitive outcomes and no differences in OS. Selected people with multiple brain
metastases from non-small-cell lung cancer may show no difference in OS when OSC is given and
WBRT is omitted. Use of radiosensitisers, chemotherapy, or molecular targeted agents in conjunction
with WBRT remains experimental. Further trials are needed to evaluate the use of neurocognitive
protective agents and hippocampal sparing with WBRT. As well, future trials should examine
homogeneous participants with brain metastases with focus on prognostic features and molecular
markers.’ (132)
MGMT promoter methylation appears to be a predictive biomarker of radiation response: in
patients who received radiotherapy alone following resection, methylation of the MGMT promoter
correlated with an improved response to radiotherapy. (133)
Tumour-treating fields (TTFields or OptuneTM, Novocure, Jersey, UK) uses localized delivery of low-
intensity, intermediate-frequency, alternating electric fields (via a specialized helmet worn for > 18
hours/day) to inhibit tumour growth by disrupting mitosis, inducing cell cycle arrest, and
59
apoptosis.(134) TTFields has been called a “fourth cancer treatment modality,” after surgery,
radiotherapy, and pharmacotherapy, as reviewed by Mun et al., 2018. (135)
A systematic review was conducted regarding the relevant studies published between January 1,
2000, and May 31, 2017 in the PubMed database. Two randomized phase III trials evaluated the
efficacy and safety of TTFields in GBM patients. The combination of TTFields and TMZ prolonged the
progression-free survival (PFS) and overall survival (OS) without systemic safety issues in newly
diagnosed GBM patients (EF-14 trial). However, for recurrent GBM, ‘the efficacy of TTFields
monotherapy was shown to be equivalent in PFS and OS without systemic adverse events when
compared to the control group that received best physicians-chosen chemotherapies (EF-11 trial).’
(136)
While TTFields has subsequently gained in popularity, some authorities have raised concern over the
lack of a sham placebo device in the trial, the invasive nature of the device in terms of the patient
experience, and the incompletely understood anti-tumour mechanism. (137) Nonetheless, TTFields
received FDA approval for patients with newly diagnosed GBM who are without contraindications in
October 2015. (137)
In March 2018 the National Comprehensive Cancer Network (NCCN) updated its clinical practice
guidelines to recommend TTFields in combination with TMZ as a category 1 treatment for newly
diagnosed GBM. (138) This treatment is not currently available in Australia.
Improved knowledge of the molecular pathogenesis of GBM biology has allowed for the
identification of new therapeutic strategies (as summarised in
60
Figure 13), and a number of targeted agents have since been developed (see Table 8). (43)
However, due to the complexity of the glioblastoma (i.e., cellular, genetic and phenotypic
heterogeneity), it is likely that a combination of molecular therapies will be necessary. (20, 39)
Over the last decade, a number of clinical studies have been completed (Table 9), and some are
ongoing (Table 10).
61
Figure 13: Molecular mechanisms of glioblastoma (GBM) pathologies and therapeutic strategies for GBM treatment. From Cai and Sughrue, 2018. (20)
62
Table 8: Selected targeted agents for GBM in clinical trials in 2010. From Quant et al., 2010.
63
Table 9. Major studies completed during the last three years (2015–2017). From Paolilo et al., 2018. (139)
64
Table 10. Major ongoing clinical trials based on pharmacological treatment(s) of malignant glioma. From Paolilo et al., 2018. (139)
Drug(s) Condition Completion date Phase NCT number 1 Bevacizumab Glioblastoma
Multiform January 2018 1,2 NCT01811498
1 Bevacizumab Glioblastoma May 2018 2 NCT02157103 1 Bevacizumab 2 Temozolomide Dietary Supplement Vitamin C
Malignant Glioma March 2020 1,2 NCT01891747
1 Bevacizumab 2 Temozolomide
Glioblastoma January 2019 2 NCT01149850
1 Bevacizumab 2 Temozolomide
Recurrent Glioblastoma
July 2023 3 NCT02761070
3 Cetuximab Glioblastoma June 2019 1,2 NCT02861898
CerebracaWafer 2 n-butylidenephthalide (BP)
Recurrent High-Grade Glioma
August 2019 1,2 NCT03234595
2 TH-302 1 Bevacizumab Glioblastoma July 2018 2 NCT02342379 2 Temozolomide Metformin Glioblastoma December 2018 2 NCT03243851 2 VAL-083 (Dianhydrogalactitol) 2 Temozolomide or 2 Lomustine or 2 Carboplatin
Glioblastoma Multiform
August 2019 3 NCT03149575
4 Capecitabine 2 Temozolomide
Glioblastoma Multiform Glioblastoma
June 2021 1,2 NCT03213002
6 Cisplatin 2 Temozolomide
High-Grade Glioma December 2017 2 NCT02263105
7 SGT-53 2 Temozolomide
Recurrent Glioblastoma
December 2019 2 NCT02340156
8 Cediranib Maleate 9 Olaparib 1 Bevacizumab
Recurrent Glioblastoma
October 2019 2 NCT02974621
10 Neratinib 3 CC-115 11 Abemaciclib 2 Temozolomide
Glioblastoma May 2021 2 NCT02977780
12 Nivolumab 1 Bevacizumab 13 Ipilimumab
Recurrent Glioblastoma
January 2018 3 NCT02017717
14 Toca 511 14 Toca FC 2 Lomustine 2 Temozolomide 1 Bevacizumab
Glioblastoma Multiform
September 2019 2,3 NCT02414165
14 VB-111 1 Bevacizumab Glioblastoma December 2017 (primary outcome)
3 NCT02511405
Dendritic cell vaccine plus 2 Temozolomide
Glioblastoma Multiform
December 2019 1,2 NCT02649582
alpha-IFN 2 Temozolomide Glioblastoma December 2017 3 NCT02496988
CIK (Cytokine-Induced Killer Cells) 2 Temozolomide
Advanced Malignant Glioma
July 2030 4
15 DNX-2401With Interferon Gamma (IFN-γ)
Recurrent Glioblastoma or Gliosarcoma Brain Tumors
August 2018 1 NCT02197169
15 DNX-2401 16 Pembrolizumab
Brain Cancer Glioma Glioblastoma
June 2020 2 NCT02798406
1 VGEF-inhibitor; 2 alchilating agent; 3 EGFR-inhibitor; 4 Thymidylate synthase inhibitor; 5 mTOR (mammalian target of rapamycin)-inhibitor; 6
DNA-binding inhibitor; 7 liposome encapsulating the wtp53 DNA sequence; 8 VEGFR inhibitor; 9 PARP inhibitor; 10 tyrosine kinase inhibitor; 11 Dual Inhibitor of CDK4 (cycline dependent kinase) and CDK6; 12 anti PD-1R (programmed death receptor) antibody; 13 anti CTLA4
(cytotoxic T-lymphocyte antigen 4)-antibody; 14 oncolytic virotherapy; 15 oncolytic adenovirus; 16 anti PD-1.
65
A number of monoclonal antibodies (mAbs) have been developed that target wtEGFR and EGFRvIII
(including cetuximab, panitumumab, and nimotuzumab) by binding to the extracellular EGFR
domain. These have shown varying effects in clinical trials for the treatment of GBM.
A phase II study involving patients stratified on the basis of EGFR gene amplification status, who
received cetuximab intravenously, had little effect and the median overall survival was 5 months.
(140) Other clinical trials involving similar antibody-based therapies have been equally unsuccessful.
(141)The limited success of EGFR inhibitors for the treatment of GBM in clinical trials may be due to
the fact that EGFR alterations represent late events that occur in only a fraction of tumour cells. (39)
The anti-angiogenic agent bevacizumab (a humanised mAb that targets VEGF) has shown PFS benefit
but not OS benefit in two phase III randomized trials. (39) However, as there is a slight increase in
the rate of adverse events (particularly thromboembolic and haemorrhagic events) among patients
taking bevacizumab, it is currently only recommended in carefully selected patients in the newly
diagnosed setting. (39)
A 2016 systematic review and meta-analysis of three trials investigating first-line use of bevacizumab
together with RT and TMZ found bevacizumab therapy did not increase median OS (pooled hazard
ratio (HR), 1.04; 95% confidence interval (CI), 0.84–1.29; P=0.71) but increased PFS (HR, 0.74; 95% CI,
0.62–0.88; P=0.0009). However, the two randomized double-blind placebo-control trials included in
the analysis found a high rate of adverse events (such as deep vein thrombosis, gastrointestinal
perforations, and hemorrhage) in the bevacizumab arm compared with placebo. (142)
The use of mAbs linked to cytotoxic molecules that specifically target cancer cells is under
investigation for the use in GBM patients as reviewed by Gan et al., 2017. (143) For example, the use
of anti-EGFR mAbs conjugated with inhibitors of microtubules assembly may provide benefits in the
treatment of gliomas. Phase I and II clinical trials of the use of these ADCs alone or in combination
with TMZ are ongoing, and preliminary results indicate a good and selective uptake of these
conjugates by tumour cells and a tolerable toxicity profile, limited to retinal toxicity. (143)
Some other emerging targeted therapies based on mutational status include small molecule IDH
inhibitors, which are in early-phase clinical trials, (144) and synthetic lethal approaches to target
IDH-mutant tumours. (39) Histone H3 K27M tumours may benefit from treatment with agents that
regulate epigenetic pathways, and BRAF inhibitors may be effective in cases with rare activating
BRAF mutations (identified in 3%–5% of GBM cases). (39)
A phase I trial (NCT01962532) using JNJ-42757493 to treat two patients with FGFR3-TACC3 fusions
showed clinical benefits; a phase II trial (NCT01975701) using the drug BGJ398 targeting FGFR3-
TACC3 fusions was completed in December, 2015. (20)
Neutrotrophic tyrosine kinase receptor type (NTRK) fusions are found in 40% of non-brain stem
paediatric high-grade gliomas in infants < 3 years old. Larotrectinib (LOXO-101) is a TRK inhibitor and
66
preliminary results from the NAVIGATE Phase 2 trial showed its potential role in treating NTRK
fusion-positive recurrent GBM. (145)
The past five years have seen an explosion in laboratory and clinical research investigating
immunotherapeutic approaches such as vaccines, adoptive T-cell therapies, and immune checkpoint
molecules for the treatment of brain cancer.
GBMs are known to create an immunosuppressive tumour microenvironment via numerous
mechanisms (e.g., by decreasing MHC expression, increasing PD-L1 expression, and secreting anti-
inflammatory IL-10). Active immunotherapy relies on stimulation of the patient’s immune system to
increase the immune response to target tumour cells. This is achieved by either boosting the entire
immune system or by training the immune system to attack the tumour specifically via tumour
antigens. (146)
To date the immunotherapy strategies that have been used for glioma can be divided into three
broad categories:
i. Immune priming (active immunotherapy) – sensitisation of immune cells to tumour antigens
using various vaccination protocols
ii. Immunomodulation (passive immunotherapy) – involves targeting cytokines in the tumour
microenvironment or using immune molecules to specifically target tumour cells
iii. Adoptive immunotherapy - involves harvesting the patient's immune cells, followed by
activation and expansion in the laboratory prior to re-infusion. (147, 148)
Compared to other tumours, the blood brain barrier (BBB) and lack of lymphatic drainage in the
brain have both been obstacles to research into this area. The BBB separates the peripheral
circulation and the CNS, preventing immune cells and antibodies from crossing into the brain.
Instead, the microglia perform immune function in the brain. (146) Evidence of the role of T cells
within glioma has led to the development of novel immunotherapeutic strategies, including immune
checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and vaccines. (147)
Peptide vaccines, such as mutated form of EGFR protein (EGFRvIII), or dendritic cell vaccines (in
which dendrocytes are loaded with tumour associated antigens and returned the patient so that a T
cells immune mediated response to those antigens can be raised), as well as immune checkpoint
inhibitors (anti-PD-1 and anti-CTLA-4) have been studied in clinical phase II/III trials and
demonstrated improved overall survival for the patients (as reviewed by Dunn-Pirio and Vlahoviv,
2017 (149)). Currently, at least three immunotherapies are in phase III clinical trials. Immunotherapy
for gliomas is comprehensively reviewed by Platten et al., 2018 (150).
Platten (2018) concludes: “Although nuances exist regarding immune responses in the CNS, effective
and dynamic immune responses are capable of being achieved in the brain and should not dampen
enthusiasm for immunotherapy approaches for neurooncology. High-grade gliomas remain a major
challenge in modern oncology. They are relatively “cold” tumors from an immunologic perspective
and exploit multiple mechanisms of immunosuppression to evade antitumor immune
responses.”(150)
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Immune checkpoint inhibitors block proteins on the surface of immune cells and sometimes cancer
cells. The function of these surface proteins is to keep immune responses in check i.e., they prevent
immune cells from being over-active. Cancer cells can exploit immune checkpoints in order to
prevent and suppress the immune system from attacking them. However, when these proteins are
blocked, it enables immune cells such as T-cells to target cancer cells more effectively (Figure 14).
Checkpoint proteins found on T cells or cancer cells include PD-1/PD-L1 and CTLA-4/B7-1/B7-2.(151)
Figure 14. Immune checkpoint inhibition. Adapted from Huang et al. 2017. (151)
When the PD-L1 protein is expressed on GBM tumour cells it binds to PD-1 and prevents the normal
immune response by T cells. PD-1 inhibitors (such as nivolumab, labrolizumab, pidilizumab) and PD-
L1 inhibitors (such as BMS-936559, MPDL3280A, MEDI4736) unblock this mechanism and allow the T
cells to destroy GBM tumour cells in the normal way.
A 2016 study showed that immune checkpoint blockade resulted in tumour eradication in an
immunocompetent glioblastoma model. (152) The authors stated that: ‘Our results support
prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well
as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.’ (152)
Several checkpoint inhibitors are advancing to late-stage clinical trials in patients with GBM e.g.,
MEDI4736 in a phase II trial. (150) A phase III clinical trial comparing a PD-1 inhibitor (nivolumab)
against an anti-VEGF mAb (bevacizumab) in patients with recurrent GBM that has is currently
enrolling patients (NCT02017717). (
68
Table 11)
69
Table 11. Clinical trials of immune checkpoint inhibitors in glioblastoma (151)
A number of vaccine approaches have been evaluated for GBM (Table 12). (150) Cancer vaccines
work by programming the immune system attack tumour cells. A number of different approaches to
cancer treatment vaccines have been tested. Some use cancer cells, parts of cancer cells, or pure
antigens; some strategies involve a patient’s own immune cells (autologous cells) being removed
and exposed to tumour cells in the lab to create the vaccine which is then injected back into the
body to increase the immune response.
The use of dendritic cell vaccines has been analysed in a review of 21 studies, including both
patients with recurrent and newly diagnosed GBM. Overall, the studies suggest that vaccination with
autologous (from the same person) dendritic cells that are loaded with autologous tumour cells
increase progression-free and overall survival when administered as adjuvant; however, large
randomised clinical trials were recommended by the authors to confirm this trend. (146)
The use of the EGFRvIII vaccine (rindopepimut), which comprises a synthetic peptide derived from
the tumour-specific mutated segment of EGFRvIII (PEP-3) conjugated to keyhole limpet hemocyanin
70
(PEPvIII-KLH) has been examined in four separate GBM trials (reviewed by Paolilo et al., 2018 (139)).
Despite previous promising results, final data analysis of a randomized, placebo-controlled, phase III
clinical trial demonstrated no survival benefit for patients with EGFRvIII-positive GBM who received
rindopepimut with temozolomide versus those who received a control. (153)
Table 12. Vaccine trials for glioblastoma. From Platten et al., 2018. (150)
A phase I study in patients with newly diagnosed MGMT-promoter unmethylated glioblastoma is
underway to test the safety and immunogenicity of a personalised peptide vaccine (NeoVax)
encompassing neoepitopes relevant for the individual patient (NCT02287428). (150)
Another approach to stimulate a vaccine effect is the use of autologous tumour cells or peptides
mixed with an adjuvant to stimulate an immune response.
Gene transfer can also be used to create a vaccine in situ by direct transfer of a specific antigenic
molecule, transfer of immune-modulating molecules, such as cytokines, or by the creation of
conditions to generate a local immune response.
CARs (chimeric antigen receptors) T cells are synthesised molecules modified to express receptors
specific for certain types of cancers. Several CAR T-cells are in clinical development for GBM
including those targeting tumour antigens such as IL-13R-α, EGFRvIII, cytomegalovirus antigens, and
HER2. (15, 150)
71
Preclinical experiments showed that GBM CAR T cells inhibited GBM growth in xenogeneic
subcutaneous and orthotopic mouse models of human EGFRvIII+ GBM and tumour regression in
combination with TMZ; a phase I trial is ongoing (NCT02209376). (154) There are currently two other
ongoing clinical trials using CAR T cells to treat GBM: one targeting the HER2 antigen (NCT01109095)
and one targeting EGFRvIII (NCT01454596). (20)
Finally, there has been one reported case of the use of CAR T cells targeting IL-13R-α2 inducing a
complete response in a patient with recurrent multifocal GBM; the patient showed improvements in
quality of life and the treatment allowed 7.5 months disease free survival. (155)
In the future, molecular characterisation of CNS tumours based on a genomic, proteomic, and
transcriptomic data will assist clinicians with the selection targeted drugs for each individual patient.
For example, knowing a person’s MGMT methylation status may influence treatment options. PTEN
may also be a useful predictive biomarker of glioma response to specific therapies. (28, 35) PTEN
may also be a useful marker of drug efficacy. Indeed, a recent study found an association between
tumours that expressed the variant EGFRvIII but still had functional PTEN and sensitivity to EGFR
inhibitor monotherapy. (28)
Only modest benefit has been observed with the currently available salvage therapies for patients
with recurrent GBM, which include re-resection, re-irradiation, and systemic therapies (primarily
nitrosoureas, TMZ, and bevacizumab). Regardless of therapy choice, overall survival is limited to 6–
12 months after recurrence. (39)
Re-irradiation as salvage therapy has been explored; however, this exposes healthy brain to
supertherapeutic doses resulting in significant rates of radionecrosis and resulting morbidity. (156)
Single-fraction SRS has been observed to have modest utility as a palliative intervention; however, it
has been associated with high rates of re-operation because of associated toxicity. (64)
Hypofractionated stereotactic radiotherapy may offer some improvement in overall survival with
minimal toxicity for patients with previously treated malignant gliomas. Hypofractionated
stereotactic radiotherapy is able to deliver treatment over two weeks with standard fractionation
schemes. In a large cohort study (n= 147) of patients with recurrent high-grade glioma,
hypofractionated stereotactic radiotherapy was observed to have with survival benefit independent
of re-operation or concomitant chemotherapy and in addition was well tolerated with minimal
adverse effects. (125)
A number of major clinical trials are currently underway worldwide and in Australia, of
pharmaceutical agents (Table 10) and vaccines (Table 12) (Appendix 2; Table 13). An overview of
recent developments in treatment of glioblastoma is shown in Figure 15.(157)
72
Figure 15. Emerging glioblastoma treatments based on chemical/immunological mechanisms [from Alphandery et al. (2018) reproduced under Creative Commons Attribution Licence (157)]
The main gene therapy strategies that have been investigated in GBM include suicide genes,
immunomodulatory genes (to enhance anti-tumour responses), tumour suppressor genes, and
oncolytic virotherapy. (158, 159)
Suicide gene therapy has been the most commonly used gene therapy using the enzyme-prodrug
suicide gene therapy system. In this approach, viral vectors or cell carriers are genetically modified
to express genes for an enzyme that can convert an inactive pro-drug into toxic metabolites at the
tumour site. To date, around 17 different clinical trials have evaluated the use of adenoviral,
retroviral or non-viral vector based delivery methods with modest or no improvement in median
survival time. Two of the most researched suicide genes that have been trialled for GBM are the
herpes simplex type 1 thymidine kinase (HSV-tk) system and the cytosine deaminase/5-
fluorocytosine (CD/5-FC) system. (158)
Oncolytic viruses can selectively target and induce lysis of tumour cells, disrupt immunosuppression
within the tumour, and reactivate antitumor immunity. (20, 159) There are a number of candidate
viruses available for this therapy, as summarised below.
• The PVSRIPO virus is currently under investigation in a phase I trial in the treatment of
recurrent GBM patients (NCT01491893). The virus destroys the tumour cells, and then
infection stimulates the host immune system to destroy other tumour cells. This treatment
73
showed safe and appreciable efficacy and extended the overall survival rate in half of the
treated patients. (160)
• Delta-24-RGD (Arg-Gly-Asp motif) (DNX-2401) is a modified adenovirus that has shown
preclinical antitumor activity and enhanced immunity of the host. (161) Preliminary recently
published results from trials show that therapy with DNX-2401 in combination with TMZ or
interferon- is well tolerated and shows significant therapeutic activity. (162)
• The human orthoreovirus (also referred to as reovirus) has been shown to infect tumour
cells in both high-grade gliomas and brain metastases, increases cytotoxic T cell tumour
infiltration, and upregulates IFN-regulated gene expression relative to patients not treated
with virus. (163)
• VB-111 is a non-replicating adenovirus containing a proapoptotic human Fas-chimera
transgene directed by a modified murine pre-proendothelin promoter, which specifically
targets endothelial cells within the tumour vasculature to induce apoptosis of these vessels.
A clinical phase II trial (NCT01260506) evaluating the safety, tolerability and efficacy of VB-
111 in 62 recurrent GBM patients is ongoing. (20)
• ADV-TK is an adenoviral vector engineered to express the Herpes thymidine kinase gene
followed by administration of an anti-herpetic prodrug (ganciclovir—GCV). A randomized
phase II clinical trial demonstrated PFS and OS benefit associated with ADV-TK gene
therapy, with a good safety profile. (164)
More recently it has been suggested that combining oncolytic virus therapy with immunotherapy
strategies (such as immune checkpoint modulation) may be both an effective and specific cancer
therapy. For example, intratumoral injection of Delta-24-RGD and an anti-PD-L1 antibody resulted in
synergistic inhibition of glioma and significantly increased survival in mice. (165) Similarly, the
addition of PD-1 blockade to reovirus enhanced systemic therapy in a preclinical glioma model. (163)
Delivery of a human IFN-β gene (which has antiviral immune modulatory, antitumor, and anti-
angiogenic properties) via an AAV vector prevented tumour growth and significantly improved
survival rate in a mouse model of invasive GBM. (166)
A recent study of recurrent glioblastoma treated with recombinant poliovirus (polio-rhinovirus
chimera, PVSRIPO) in 61 patients with WHO grade IV malignant glioma to test for toxicity and dose
found that the survival rate was higher (at 24 and 36 months) compared to historical controls. (160,
167)
The use of Toca 511 (vocimagene amiretrorepvec, an injectable retroviral replicating vector
encoding a prodrug activator, cytosine deaminase) combined with Toca FC (an oral formulation of 5-
fluorocytosine that is easily absorbed and able to cross the BBB) is also under clinical investigation in
patients with high-grade glioma. (168) These agents work in combination: cytosine deaminase
converts 5-fluorocytosine to 5-FU, a widely used anti-cancer agent.
Another emerging area is nanoparticles, which have been studied as a method to overcome the
problems with getting treatments across the BBB. Magnetic nanoparticles have also been used for
imaging and diagnosis.
74
There are a number of different types of nanoparticles currently in the early phases of research and
development (Table 12). These nanoparticles can protect drug degradation, control drug release for
a sustained period of time, and reduce toxic side effects, although safety concern is still needed for
further investigation. (169)
Nanoparticles may be biodegradable polymers that can be loaded with chemotherapeutic drugs to
induce toxicity. For example, nanoparticles made from liposomes have been used to improve the
delivery of the chemotherapeutic agent paclitaxel, which is hydrophobic and problematic to get
across the BBB. (170)
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Table 12: Nanoparticles proposed as candidates for GBM treatment. Adapted from Hernandez et al., 2013.
Nanoparticle Structure Function
Liposomes Bilayered vesicles conjugated with some proteins or drugs (i.e., anfotericine) for recognition and/or lists of cancer cells
Due to their amphiphilic structure, it is feasible to manipulate surface modification and/or conjugate them with biomolecules to increase the circulating half-life and deliver antineoplastic drugs in tumoral areas
Solid lipid nanoparticles Submicron colloidal carriers that could be loaded with other types of chemotherapeutics or specific antibodies
Currently, these particles are under research, but they could deliver chemotherapeutic agents into neoplastic cells due to their biocompatible and fusionable membranes
Drugs or toxin conjugated nanoparticles
The satisfactory size of nanoparticles allows to encapsulate anti-neoplastic drugs, toxins, or specific antibodies directed to membrane-bound antigens in cancer cells
These nanoconjugates deliver their drug load to increase local levels of apoptotic molecules near tumours or to accumulate in focal areas to exert their cytotoxic effect
Nanocrystals Crystalline aggregates of hydrophobic molecules coated with a thin hydrophilic layer
Depending of the size of crystals several protein-metal conjugates can originate nanorods or nanowires which could enhance thermosensitivity of cancer cells
Nanotubes Single or multilayered sheets of self-assembling organic or inorganic atoms
Due to their large inner volume and great external surface could be drug-loaded and may induce cellular death
Dendrimers Monomeric or oligomeric multi-branched structures whose exterior-end groups can be conjugated to drugs, antibodies, or metal atoms
These symmetrical particles may encapsulate drugs, targeting moieties, antibodies, and functional groups to carry and deliver them inside tumour
Magnetic drug targeting of magnetised nanoparticles bound to anti-cancer agents is another method
under development. (171) Ferrofluids containing the magnetic particles conjugated to anti-tumour
agents are injected intravenously and then concentrated to the tumour using an external magnetic
field. Such particles may provide a new method for glioma-targeted drug delivery. (172-174)
Gold nanoparticles can be used both as contrast agent for MRI and for photothermal therapy; for
example, gold nanorods have been used in vivo for thermal ablation of glioblastoma cells. (175)
76
Dual purpose TMZ-loaded lactoferrin nanoparticles (SERP-17-12433) have also be investigated for
combating glioma in animal studies. The authors stated: ‘We strongly believe that the ability of the
nanoformulation reported here to target tumors with a high degree of specificity may allow dose
escalation and result in an improved response in glioma patients along with increasing the median
life survival.’ (176)
Finally, intravenous administration of polyethylene glycol (PEG) nanoparticles loaded with c-Met
siRNA was found to reduce c-Met expression and powerfully inhibit cell proliferation and resistance
to chemotherapeutic agents in GBM cells. (177)
Targeting cancer stem cells (CSCs) has emerged as another treatment option. Stem cells have a
multipotent function, have self-renewal potential, and show resistance to chemotherapy and
radiotherapy.
Cho et al., 2013 (178) review five methods being used to target GBM stem cells (GSCs): One is to
develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitiser to
enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a
fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing
gene therapy may be helpful. The authors conclude: ‘the combination of conventional surgery,
chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising
treatment for reducing GBM recurrence and improve the survival rate.’
In addition, delivery of miR-1 by nanoparticles has been found to efficiently target GSCs, and reduce
cell migration and proliferation. (179)
A recent study by Bago et al., 2016 (180) provided evidence that transdifferentiation (TD)-derived
induced neural stem cells (iNSCs) are tumour-homing and inhibited progression of GBM in patient-
derived GBM8 xenograft mice.
Another focus for new research has been on disruption of the BBB order to facilitate administration
of anti-cancer agents to the tumour site. Studies in animal models have found that focused
ultrasound (FUS) can enhance the penetration drugs through the BBB without causing significant
adverse effects. (181) This method delivers burst-tone ultrasound energy in the presence of
microbubbles.(181) Early clinical trials have demonstrated safety and Phase I/II trials are now
underway.(182) The researchers reported that: ‘repeated opening of the BBB using our pulsed
ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in
patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.’
(182)
Other neurosurgical technologies leading to transient BBB and blood-brain tumour barrier disruption
include: superselective intra-arterial mannitol infusion, laser interstitial thermotherapy (LITT), and
non-thermal irreversible electroporation, as reviewed by Rodriguez et al., 2015. (183)
The manipulation of the BBB microenvironment using body-identical metabolic agents and proteins
such as fatty acids, lactic acid, fibronectin, tenascin etc. could also assist in the treatment of brain
tumours in the future. As stated by Zhao et al., 2017 (184): ‘Many studies have used natural products
77
to regulate the BBB microenvironment, most of which focused on regulating oxidative stress, MMPs,
WNT/β-catenin and PI3K/AKT/BDNF/TRKB-ERK/NF-κB pathway’.
Tumour microtubes are ultra-long membranous protrusions that extend from astrocytoma cells;
they are resistant to the cytotoxic effects of both radiotherapy and TMZ and may contribute to local
recurrence after resection. (39) Therefore, pathways regulating tumour microtubule formation may
represent novel therapeutic targets. (39) For example, communication via the tumour microtubule
network could be blocked by gap junction inhibitors. (39) However, further research in this area is
required. (39)
The CRISPR/Cas9 system offers targeted and accurate genome editing, correction and repair. While
the feasibility of this approach in GBM is presently unknown, it has shown to be a promising
approach in other cancers (185) and thus requires further investigation. (20)
Depatuxizumab mafodotin (depatux-m; ABT-414) is a new treatment in development which includes
an antibody linked to a drug (called a conjugate). The antibody specifically seeks out and binds to
cells that have EGFR amplification switched on. It is then taken inside the cell and releases the drug -
an antimicrotubule agent called monomethyl auristatin F (MMAF). In an open label trial of 66 people
with recurrent GBM, monotherapy with depatux-m had a promising progression-free survival of
28.8% although a large proportion of patients displayed Grade 1/2 ocular toxicities.(186)
Recent early research has discovered that sorafenib, disulforam and metformin may have potential
with a direct effect on cancer stem cells viability in a number of tumours including GBM. (107)
Furthermore, combining metformin with chemotherapy drugs such as cisplatin or doxorubicin may
be advantageous. Metformin also improves the pro-apoptotic effect of TMZ. (107)
Sorafenib (SO) is an oral multikinase inhibitor, which targets several tyrosine kinases receptors (RTK),
involved in tumour growth progression and neoangiogenesis including VEGFR, PDGFR and fibroblast
growth factor receptor 1 (FGFR1).
Disulfiram (tetraethylthiuram disulfide, DSF) is an inhibitor of the aldehyde dehydrogenase (ALDH)
enzyme family, and in TMZ resistant GBM stem cells has been found to reduce in vitro cell growth.
Metformin is an anti-diabetic drug used to treat type II diabetes and polycystic ovary syndrome.
Patients treated with metformin exhibit reduced cancer-related mortality leading to investigations of
the potential anti-tumour effects of the drug. The exact molecular mechanism is yet to be elucidated
but studies so far point to either indirect action via the reduction of systemic levels of insulin or
glucose, or direct impact on tumour growth. (107)
Another recent review looked at repurposing older drugs that cross the BBB and have potential
anticancer activity. (187) The authors identified a number of drugs (including antidepressants, anti-
epileptic drugs, statins, beta-blockers, and other anti-hypertensive agents) that could represent
novel anti-neoplastic agents for use in GBM and are worth investigating.
78
There is currently limited evidence for the use of holistic or alternative treatments in the treatment
of glioma.
Curcumin, a component of turmeric, has been found to be an effective inhibitor of proliferation and
inducer of apoptosis in many cancers. Curcumin is thought to decrease GBM cell viability by
decreasing prosurvival proteins (e.g., NF-κB, activator protein 1, and phosphoinositide 3 kinase) and
upregulating apoptotic pathways (e.g., p21, p53, and executor caspase 3). (188)
A 2016 systematic review investigated the utility of curcumin as an antiglioma agent and identified a
total of 19 in vitro and five in vivo studies. The authors concluded that: ‘Curcumin inhibits
proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability
to target multiple signalling pathways involved in cell death makes it an attractive therapeutic agent.
As such, it should be considered as a potent anticancer treatment. Further experiments are
warranted to elucidate the use of a bioavailable form of curcumin in clinical trials.’ (188)
In a Japanese population it was observed that while coffee reduced the risk of GBM, green tea had
no significant effect. (189) There is no high-quality evidence on the effect of ketogenic diets in
oncology patients. (190)
Exercise programs have been shown to be beneficial to aid recovery from radiation treatment and
improve quality of life for survivors of paediatric brain cancer.(191-194) The use of medicinal
cannabis and its effect on outcomes for GBM patients is under investigation and results are expected
at the end of 2019 (NCT03052738). There is evidence that medicinal cannabis may have a role in
preventing chemotherapy-induced nausea and vomiting and as pain relief. It also acts as an appetite
stimulant.(195)
Outcomes following surgical resection (median survival) have been observed as:
• 10 years for low- grade oligodendroglioma
• 5–8 years for low-grade astrocytoma
• 1–7 years for anaplastic oligodendroglioma
• 3 years for anaplastic astrocytoma
• 1 year for GBM Younger age, good preoperative performance status and gross macroscopic resection are all
commonly associated with longer survival. (98)
The current standard of care for patients with newly diagnosed GBM includes maximum safe tumour
resection followed by a 6-week course of radiotherapy with concomitant systemic therapy using
TMZ and followed by 6 months of adjuvant TMZ. (94, 95) However, this treatment approach was
established based on the results of a trial that did not include patients aged >70 years. Trials in
elderly GBM patients (variably defined as patients aged ≥60–70 years of age), who have a
particularly poor prognosis, demonstrated the efficacy of shorter, hypofractionated radiotherapy
regimens, and a predictive role of MGMT-promoter methylation for benefit from first-line TMZ
79
alone. Nonetheless, elderly patients with MGMT-promoter-methylated tumours who are eligible for
combined modality treatment can benefit from the TMZ/RT→TMZ regimen. (15)
Because of the diffuse nature of GBM, focal radiotherapy techniques such as SRS are not particularly
beneficial. The use of intensity-modulated radiotherapy is popular because of its improved targeting.
(7)
Median overall survival ranges from 4–17 months and one, two- and three-year survival range from
14–70%, 0–25% and 0–10%, respectively. A variety of therapeutic strategies have been utilised in
DIPG, but there is no standard treatment. Outcomes of various clinical trials are reviewed by Jansen
et al., 2012. (51)
Some potential new therapies for paediatric DIPG are reviewed by Long et al., 2017. (196)
Surgery is the treatment of choice for ependymomas with the primary goals being to achieve
complete tumour resection and to remove obstacles to CSF flow. Surgical resection has been
significantly associated with better overall and progression-free survival. Radiotherapy is also utilised
management of intracranial ependymomas. There is limited clinical evidence for benefit and
ependymomas are thought to be relatively radioresistant. There is also a lack of evidence regarding
the use of chemotherapy but in the case of recurrence platinum-based agents have better response
rates (31–67%) compared to non-platinum-based agents (11–13%). (197)
There have been inconsistent survival outcomes in retrospective studies for ependymomas graded
histologically as II versus III. However, based on improved understanding of discrete molecular
subtypes, a molecular risk stratification algorithm has been developed to guide therapeutic
strategies in patients with ependymoma. (198)
Surgery is the first-line treatment for medulloblastoma with the aim of restoring normal CSF flow in
the case of an obstructive hydrocephalus and to achieve full resection of the tumour. Complete
resection results in a significantly better prognosis. Surgery alone is insufficient to achieve long-term
remission. Radiotherapy is the second-line treatment of choice and consensus is that therapy should
start no later than 4–6 weeks postoperatively and last no longer than 50 days.
Chemotherapy is currently given as adjuvant to the majority of patients and may be used to avoid
radiotherapy in infants. The best evidence is for chemotherapy, using lomustine, vincristine and
cisplatin for up to 8 cycles after conventional dose radiotherapy and concomitant vincristine. (52)
Molecular classification of medulloblastoma has paved the way for targeted therapies, as
comprehensively reviewed by Kumar et al., 2017. (58)
A 2017 systematic review of phase I and phase II trials involving 662 children or adolescents with
medulloblastoma/primitive neuroextodermal tumours was recently published. The authors stated:
‘Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies
was 0% (0–100) and 6.5% (0–50), respectively. Temozolomide containing regimens had a median
ORR of 16.5% (0–100). Smoothened inhibitors trials had a median ORR of 8% (3–8). Novel drugs have
80
shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone
for new combinations.’ (199)
Surgical resection and post-operative radiation therapy are recommended for WHO grade II and III
meningiomas to reduce recurrence rates. Clinical studies to assess the optimal timing and modality
of post-operative radiation are still being conducted and are reviewed by Walcott et al., 2013. (200)
A 2017 systematic review and meta-analysis found radiosurgery was a safe and effective treatment
for meningioma, with an estimated disease control rate ranging from 87.0% to 100.0% at 5 years and
from 67.0% to 100.0% at 10 years. (130) However, the authors concluded that: ‘Efforts are needed in
standardizing the definition of local and symptom control and toxicity in order to properly compare
different treatment schedules.’ (130)
Surgery is the primary treatment for IDH-mutant and 1q/19p co-deletion oligodendrogliomas. If
further treatment is considered necessary, standard treatment is radiotherapy followed by
procarbazine, lomustine, and vincristine chemotherapy. (201)
Routine medical management of oligodendroglioma now requires assessment of 1p/19q status to
deliver the best treatment. (17, 40) Anaplastic (WHO Grade III) oligodendrogliomas with 1q/19p co-
deletion are more responsive to therapy with a median survival of 3–6 years. Addition of
chemotherapy to radiotherapy prolongs progression-free and overall survival. (7, 35)
Currently, no evidence exists for the use of combined treatment with bevacizumab and cytotoxic
drugs in this setting. (201)
Losses of 1p and 19q have been observed in approximately 30–50% of oligoastrocytoma and 20–30%
of anaplastic oligoastrocytoma. (4) Median survival is 2 to 3 years for grade III astrocytoma. (7, 35)
Treatment is radiotherapy followed by adjuvant chemotherapy. (114)
MRI is the standard diagnostic measure for the evaluation of disease status or treatment response
and is typically conducted at 3-month intervals. (201)
Response to treatment is typically assessed using the 2D Response Assessment in Neuro-Oncology
(RANO) criteria, in which in addition to contrast enhancement, tumour extension on T2- and fluid-
attenuated inversion recovery (FLAIR)-weighted MRI are evaluated. However, a recent report has
suggested some modifications to the RANO criteria such as: ‘volumetric response evaluation, use
contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-
enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for
newly diagnosed glioblastoma response assessment, and “treatment-agnostic” response assessment
rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response.’ (202)
The use of liquid biopsies to examine extracellular vesicles as biomarkers for treatment response is
also a promising new area of research. (91)
81
Pseudoprogression is the term used for the changes observed after radiotherapy that mimic tumour
progression. When concomitant radiotherapy plus TMZ became the treatment of choice for
malignant glioma, the incidence of pseudoprogression increased. (203-205)
Pseudoprogression is a sub-acute reaction that results in oedema, inflammation, and increased
vessel permeability giving rise to increased contrast on MRI. This effect is found to decrease, or at
least stabilise, over time and occurs more often in those with methylated MGMT promoter tumours.
(7)
Distinguishing tumour recurrence from pseudoprogression and radiation necrosis is a frequent
difficulty in GBM treatment. (206) However, advanced imaging techniques, including perfusion
weighted imaging (PWI) for microvascular dynamics and diffusion-weighted imaging (DWI) for water
molecule diffusion are being increasingly used to more accurately distinguish pseudoprogression
from true tumour progression. (20)
The 2017 paper by Miranda et al. (207) provides an appropriate summary to this section on the
treatment of gliomas, particularly GBM:
‘Despite all the advances in oncology research, the management of patients with GBM remains one
of the greatest challenges worldwide. The current standard of care in GBM, encompassing surgical
resection with adjuvant radiotherapy and TMZ, remains the best option so far, although high rates of
treatment failure cannot be ignored. Much is already known in what concerns the limitations
imposed by the BBB, the inter- and intra-GBM heterogeneity and the drug-resistance nature of GBM
cells to TMZ, being strong predictors for tumour recurrence. This line of thinking and new data
supporting the critical role of GCSs in tumour progression have accelerated research for curing GBM.
New therapeutic approaches have been introduced for GBM in recent years, bearing in mind the
efforts to overcome natural barriers to reach the tumour mass and then eradicate it. Direct delivery
into the brain, immunotherapy, genomics, and nanotechnology stand out as promising strategies due
to their recent key advances in management of GBM. It is noteworthy, however, that many of those
promising findings still require further investigation prior to their potential clinical translation.’
The 2017 paper by Reifenberger et al. (207) provides an appropriate summary to this updated
review:
‘Advances in molecular profiling technologies have enabled the characterization of genetic and
epigenetic changes in gliomas at a hitherto unprecedented level of detail. New biomarkers have been
identified that can improve the diagnostic accuracy and guide the use of individualized treatments.
These developments have led to the 2016 update of the WHO Classification of Tumours of the CNS
that breaks with the traditional approach of purely histology-based glioma diagnostics by incorporat-
ing molecular biomarkers into an integrated diagnosis. In parallel, improved knowledge of glioma
biology has provided opportunities for novel pathogenesis-based pharmacological treatments and
innovative immunotherapeutic strategies; for example, new strategies for targeting tumour-
associated mutant proteins or immune checkpoints have emerged. Moreover, innovative trial
82
concepts have been initiated that involve predictive molecular profiling followed by individualized
therapy specifically tailored to the characteristics of each tumour. Thus, the time has come to expand
the implementation of precision medicine in neuro-oncology.’
83
Table 1: P53 mutations and their impact on glioblastoma (GBM). From England et al., 2013. (22) .................... 17
Table 2: Main molecular markers used in the diagnosis of CNS Tumours. From Gupta and Dwivedi, 2017. (49) 33
Table 3: Other molecular markers associated with glioma. From Ludwig & Kornblum, 2017. (74) ..................... 34
Table 4: Grading of selected CNS tumours according to the 2016 CNS WHO. From Louis et al., 2016................ 35
Table 5: Molecular biomarkers and their clinical relevance in gliomas. From Siegal, 2015. (88) ......................... 39
Table 6: Molecular and metabolic alterations in GBM and their potential biomarker status. From McNamara et
al., 2013. (35) ............................................................................................................................................... 40
Table 7: Prognostic/predictive molecular markers in high-grade gliomas. From Masui et al., 2012. (4) ............. 40
Table 8: Selected targeted agents for GBM in clinical trials in 2010. From Quant et al., 2010. ........................... 53
Table 9. Major studies completed during the last three years (2015–2017). From Paolilo et al., 2018. (139) .... 54
Table 10. Major ongoing clinical trials based on pharmacological treatment(s) of malignant glioma. From
Paolilo et al., 2018. (139) ............................................................................................................................. 55
Table 11. Clinical trials of immune checkpoint inhibitors in glioblastoma (151) .................................................. 59
Table 12. Vaccine trials for glioblastoma. From Platten et al., 2018. (150) .......................................................... 60
Table 13. Australian clinical trials currently recruiting. ........................................................................................ 75
Figure 1: Number of publications on the topic of glioblastoma in PubMed showing rapid growth of interest in
this field of research. ..................................................................................................................................... 7
Figure 2: New cases of brain and other CNS cancer, by site and life stage, 2013 (AIHW ACD 2013) .................. 11
Figure 3: Five-year survival rate (%) from 1984 to 2013. Source data: AIHW. (3) ................................................ 12
Figure 4: Pathways to glioblastoma. Adapted from Hays et al., 2017. (18) ......................................................... 14
Figure 5: Common pathways to primary and secondary glioblastoma (GBM), and pilocytic astrocytoma (PA).
Adapted from Gupta et al., 2012. (19) ......................................................................................................... 15
Figure 6: Novel signalling pathways identified to contribute to glioblastoma (GBM) development. From Cai &
Sughrue (2018). (20) .................................................................................................................................... 16
Figure 7: Enzymatic activities of wild type and mutated IDH enzymes. (From Mondesir et al. 2016) (1) ............ 19
Figure 8: Emerging genetic alterations in GBM. The mutational spectrum and molecular mechanisms thought
to promote tumorigenesis for IDH1 and IDH2, TERT, ATRX, H3F3A, and HIST1H3B. From Reitman et al.,
2018. (39) ..................................................................................................................................................... 21
Figure 9. EANO guideline Clinical pathway for glioma - maximum safe resection is recommended whenever
feasible in all patients with newly diagnosed gliomas. (70)......................................................................... 29
Figure 10. Summary of NICE guidelines for management options for people with newly diagnosed Grade IV
glioblastoma. [Note: KPS = Karnofsky performance status; age is approximately 70 years; for people not
covered by these options other suggestions are included in the guideline.](63) ........................................ 32
Figure 11. Conclusions, recommendations and levels of evidence from the CGCG. (72) .................................... 32
Figure 12: Positive and negative predictors of long-term survival in patients with glioblastoma (GBM). From
Chaudhry et al., 2013. (83) .......................................................................................................................... 37
Figure 13: Molecular mechanisms of glioblastoma (GBM) pathologies and therapeutic strategies for GBM
treatment. From Cai and Sughrue, 2018. (20) ............................................................................................. 52
Figure 14. Immune checkpoint inhibition. Adapted from Huang et al. 2017. (151) ............................................. 58
Figure 15. Emerging glioblastoma treatments based on chemical/immunological mechanisms [from
Alphandery et al. (2018) reproduced under Creative Commons Attribution Licence (157)]....................... 62
84
• (GBM OR glioblastoma glioblastoma multiforme OR brain cancer) AND p53 OR TP53
• (GBM OR glioblastoma glioblastoma multiforme OR oligodendroglioma OR brain cancer)
AND 1p OR 19q
• (GBM OR glioblastoma multiforme OR brain cancer) AND (EGFR OR PTEN)
• (GBM OR glioblastoma multiforme OR brain cancer) AND IDH1
• PDL1
• Pilocytic Astrocytomas AND (treatment OR surgery OR radio*)
• (GBM OR glioblastoma multiforme OR oligodendroglioma OR brain cancer) AND
(treatment OR surgery OR radio* OR chemo*)
• (Diffuse Intrinsic Pontine Glioma OR DIPG) AND (treatment OR surgery OR radio* OR
chemo*)
• CNS Lymphoma AND (treatment OR surgery OR radio* OR chemo*)
• Ependymoma AND (treatment OR surgery OR radio* OR chemo*)
• Medulloblastoma AND (treatment OR surgery OR radio* OR chemo*)
• Meningioma AND (treatment OR surgery OR radio* OR chemo*)
• (Oligoastrocytoma OR Oligodendroglioma) AND treatment OR surgery OR radio* OR
chemo*)
(GBM[All Fields] OR (("glioblastoma"[MeSH Terms] OR "glioblastoma"[All Fields]) AND
("glioblastoma"[MeSH Terms] OR "glioblastoma"[All Fields] OR ("glioblastoma"[All Fields] AND
"multiforme"[All Fields]) OR "glioblastoma multiforme"[All Fields])) OR ("brain neoplasms"[MeSH
Terms] OR ("brain"[All Fields] AND "neoplasms"[All Fields]) OR "brain neoplasms"[All Fields] OR
("brain"[All Fields] AND "cancer"[All Fields]) OR "brain cancer"[All Fields])) AND (p53[All Fields] OR
TP53[All Fields]) AND ((Randomized Controlled Trial[ptyp] OR Practice Guideline[ptyp] OR
systematic[sb] OR Meta-Analysis[ptyp]) AND hasabstract[text] AND "2013/03/09"[PDat] :
"2018/03/07"[PDat] AND "humans"[MeSH Terms])
(GBM[All Fields] OR ("glioblastoma"[MeSH Terms] OR "glioblastoma"[All Fields] OR
("glioblastoma"[All Fields] AND "multiforme"[All Fields]) OR "glioblastoma multiforme"[All Fields])
OR ("brain neoplasms"[MeSH Terms] OR ("brain"[All Fields] AND "neoplasms"[All Fields]) OR "brain
neoplasms"[All Fields] OR ("brain"[All Fields] AND "cancer"[All Fields]) OR "brain cancer"[All Fields]))
AND (EGFR[All Fields] OR PTEN[All Fields]) AND ((Practice Guideline[ptyp] OR Randomized Controlled
Trial[ptyp] OR systematic[sb] OR Meta-Analysis[ptyp]) AND "2013/03/09"[PDat] :
"2018/03/07"[PDat] AND "humans"[MeSH Terms])
85
The Australian Clinical Trials Registry was searched for brain cancer trials that are currently recruiting
in April 2018. In total 38 records were identified, of which 5 were excluded as they are investigations
of secondary brain cancer/metastases. The relevant trials are listed in Table 13.
Table 13. Australian clinical trials currently recruiting.
Trial ID Study name Phase ACTRN12618000006246 Access to Innovative Molecular Diagnostic PROfiling for Paediatric
Brain Tumours
N/A
ACTRN12618000003279 An Open-Label Trial to Investigate the Safety, Tolerability,
Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in
Combination with AGEN2034 in Patients with Metastatic or Locally
Advanced Solid Tumours
Phase I/II
ACTRN12617000534381 A Randomised Phase II Trial to Examine Feasibility of Standardised,
Early Palliative (STEP) Care for Patients with Advanced Cancer and their
Families
Phase II
ACTRN12617000507381 A feasibility study of hair sparing whole brain radiotherapy with
volumetric modulated arc therapy for patients who have brain
metastases from any malignancy. (The Hair Spare Study)
N/A
ACTRN12617000267358 A Randomised Phase II Study of NivolUmab and TeMozolomide vs
Temozolomide alone in newly diagnosed Elderly patients with
Glioblastoma (NUTMEG)
Phase II
ACTRN12617000078358 Perampanel for the control of glioma associated seizures – efficacy and
safety
Phase II
ACTRN12616001350415 The efficacy of histone deacetylase inhibitor valproic acid in the
treatment of gliomas
Phase IV
ACTRN12616000874415 Pilot feasibility study of Exercise in grade III and IV High Grade Glioma
(glioblastoma & anaplastic astrocytomas) while undergoing up-front
Radiation with or without chemotherapy (EGGR study)
N/A
ACTRN12616000863437 Functional MRI assessment of primary and secondary brain tumour
response to radiation therapy: A pilot study
Pilot study
ACTRN12615001202550 Study to assess the neurological and cognitive effects of using
Hypofractionated Stereotactic Radiotherapy used to treat multiple (3-
10) brain metastases.
Phase II
ACTRN12615001182583 The AGOG (Australian Genomics and Clinical Outcomes of Glioma)
Epidemiology Study - investigating lifestyle and environmental
exposures and genetic variants and glioma risk in those with and
without glioma.
N/A
ACTRN12615001072505 A Phase II randomised placebo-controlled, double blind, multisite study
of Acetazolamide versus placebo for management of cerebral oedema
in recurrent and/or progressive High Grade Glioma requiring treatment
with Dexamethasone – The ACED trial
Phase II
ACTRN12615000407594 A Randomised Phase II study of Veliparib, Radiotherapy and
Temozolomide in patients with unmethylated O (6)-methylguanine-
DNA methyltransferase (MGMT) Glioblastoma (brain cancer) (VERTU
study)
Phase II
ACTRN12614001114639 Determining prognosis and treatment response: novel imaging
modalities for Glioblastoma
N/A
86
ACTRN12612001183875 Diffuse Brainstem Glioma Tumour Study: developing new treatment
strategies for Diffuse Pontine Glioma
N/A
ACTRN12611000574943 Treatment of Anxiety and Depression in Adult Brain Tumour Patients N/A
ACTRN12609000877280 Development of Magnetic Resonance Imaging - Positron Emission
Tomography (MRI-PET) Image Biomarkers for Brain Tumour Grading,
Delineation and Measuring Early Treatment Response
N/A
NCT03374943 A Trial of KB004 in Patients With Glioblastoma Phase I
NCT03296696 Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma Phase I
NCT02687386 A Study of Intravenous EEDVsMit in Children With Recurrent /
Refractory Solid or CNS Tumours Expressing EGFR
Phase I
NCT02667587 An Investigational Immuno-therapy Study of Temozolomide Plus
Radiation Therapy With Nivolumab or Placebo, for Newly Diagnosed
Patients With Glioblastoma (GBM, a Malignant Brain Cancer)
Phase III
NCT02637687 Oral TRK Inhibitor LOXO-101 (Larotrectinib) for Treatment of Advanced
Pediatric Solid or Primary Central Nervous System Tumors
Phase I/II
NCT02617589 An Investigational Immuno-therapy Study of Nivolumab Compared to
Temozolomide, Each Given With Radiation Therapy, for Newly-
diagnosed Patients With Glioblastoma (GBM, a Malignant Brain
Cancer)
Phase III
NCT02568267 Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients
With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK
Gene Rearrangements (Fusions)
Phase II
NCT02573324 A Study of ABT-414 in Subjects With Newly Diagnosed Glioblastoma
(GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification
Phase III
NCT02343406 Adult Study: ABT-414 Alone or ABT-414 Plus Temozolomide vs.
Lomustine or Temozolomide for Recurrent Glioblastoma Pediatric
Study: Evaluation of ABT-414 in Children With High Grade Gliomas
Phase II
NCT02296580 A Feasibility Study of the Nativis Voyager® System in Patients With
Recurrent Glioblastoma Multiforme (GBM)
N/A
NCT02176967 Response and Biology-Based Risk Factor-Guided Therapy in Treating
Younger Patients With Non-high Risk Neuroblastoma
Phase III
NCT01878617 A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed
Medulloblastoma
Phase II
NCT01677741 A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral
Dabrafenib In Children and Adolescent Subjects
Phase I
NCT01096368 Maintenance Chemotherapy or Observation Following Induction
Chemotherapy and Radiation Therapy in Treating Younger Patients
With Newly Diagnosed Ependymoma
Phase III
NCT00904241 Biomarkers in Tumor Tissue Samples From Patients With Newly
Diagnosed Neuroblastoma or Ganglioneuroblastoma
N/A
NCT00392327 Chemotherapy and Radiation Therapy in Treating Young Patients With
Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma
Phase III
87
1. Mondesir J, Willekens C, Touat M, de Botton S. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. Journal of blood medicine. 2016;7:171-80. 2. Australian Institute of Health and Welfare. Brain and other central nervous system cancers. 2018. 3. Australian Institute of Health and Welfare. Cancer in Australia 2017 2017. 4. Masui K, Cloughesy TF, Mischel PS. Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathology and applied neurobiology. 2012;38(3):271-91. 5. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-20. 6. Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il'yasova D, et al. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer. 2008;113(7 Suppl):1953-68. 7. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA : the journal of the American Medical Association. 2013;310(17):1842-50. 8. Linos E, Raine T, Alonso A, Michaud D. Atopy and risk of brain tumors: a meta-analysis. J Natl Cancer Inst. 2007;99(20):1544-50. 9. Amirian ES, Zhou R, Wrensch MR, Olson SH, Scheurer ME, Il'yasova D, et al. Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study. Cancer Epidemiol Biomarkers Prev. 2016;25(2):282-90. 10. Melin BS, Barnholtz-Sloan JS, Wrensch MR, Johansen C, Il'yasova D, Kinnersley B, et al. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat Genet. 2017;49(5):789-94. 11. Johansson G, Andersson U, Melin B. Recent developments in brain tumor predisposing syndromes. Acta oncologica (Stockholm, Sweden). 2016;55(4):401-11. 12. Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061-8. 13. Taylor TE, Furnari FB, Cavenee WK. Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance. Curr Cancer Drug Targets. 2012;12(3):197-209. 14. Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. Journal of neuro-oncology. 2012;108(1):11-27. 15. Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M. Advances in the molecular genetics of gliomas - implications for classification and therapy. Nature reviews Clinical oncology. 2017;14(7):434-52. 16. Karsy M, Gelbman M, Shah P, Balumbu O, Moy F, Arslan E. Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features. Folia Neuropathol. 2012;50(4):301-21. 17. Alentorn A, Sanson M, Idbaih A. Oligodendrogliomas: new insights from the genetics and perspectives. Current opinion in oncology. 2012;24(6):687-93. 18. Hays EM, Duan W, Shigdar S. Aptamers and Glioblastoma: Their Potential Use for Imaging and Therapeutic Applications. Int J Mol Sci. 2017;18(12). 19. Gupta K, Salunke P. Molecular markers of glioma: an update on recent progress and perspectives. Journal of cancer research and clinical oncology. 2012;138(12):1971-81. 20. Cai X, Sughrue ME. Glioblastoma: new therapeutic strategies to address cellular and genomic complexity. Oncotarget. 2018;9(10):9540-54. 21. Gilheeney SW, Kieran MW. Differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters. Future Oncol. 2012;8(5):549-8.
88
22. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2013;34(4):2063-74. 23. Toraih EA, Aly NM, Abdallah HY, Al-Qahtani SA, Shaalan AA, Hussein MH, et al. MicroRNA-target cross-talks: Key players in glioblastoma multiforme. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2017;39(11):1010428317726842. 24. Martinez R. Beyond genetics in glioma pathways: the ever-increasing crosstalk between epigenomic and genomic events. Journal of Signal Transduction. 2012;2012:5159807. 25. Hegi ME, Rajakannu P, Weller M. Epidermal growth factor receptor: a re-emerging target in glioblastoma. Current opinion in neurology. 2012;25(6):774-9. 26. Kalman B, Szep E, Garzuly F, Post DE. Epidermal growth factor receptor as a therapeutic target in glioblastoma. Neuromolecular medicine. 2013;15(2):420-34. 27. Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. The Journal of pathology. 2014;232(2):165-77. 28. Camara-Quintana JQ, Nitta RT, Li G. Pathology: commonly monitored glioblastoma markers: EFGR, EGFRvIII, PTEN, and MGMT. Neurosurgery clinics of North America. 2012;23(2):237-46, viii. 29. Johnson DR, Chang SM. Recent medical management of glioblastoma. Adv Exp Med Biol. 2012;746:26-40. 30. Gao Q, Lei T, Ye F. Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma. Expert Opin Investig Drugs. 2013;22(8):1023-40. 31. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. The New England journal of medicine. 2009;360(8):765-73. 32. Weller M, Pfister SM, Wick W, Hegi ME, Reifenberger G, Stupp R. Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol. 2013;14(9):e370-9. 33. Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene. 1998;16(17):2259-64. 34. Steck PA, Pershouse MA, Jasser SA, Yung WKA, Lin HL, Ligon AH, et al. Identification of candidate tumour suppressor gene, MMAC1, at chormosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genetics. 1997;15:356. 35. McNamara MG, Sahebjam S, Mason WP. Emerging biomarkers in glioblastoma. Cancers (Basel). 2013;5(3):1103-19. 36. Kwon CH, Zhao D, Chen J, Alcantara S, Li Y, Burns DK, et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer research. 2008;68(9):3286-94. 37. Thiessen B, Maguire JA, McNeil K, Huntsman D, Martin MA, Horsman D. Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligodendroglial tumors: relationship to outcome and chemosensitivity. Journal of neuro-oncology. 2003;64(3):271-8. 38. Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455(7216):1129-33. 39. Reitman ZJ, Winkler F, Elia AEH. New Directions in the Treatment of Glioblastoma. Semin Neurol. 2018;38(1):50-61. 40. Anderson MD, Gilbert MR. Treatment recommendations for anaplastic oligodendrogliomas that are codeleted. Oncology. 2013;27(4):315-20, 22. 41. Frattini V, Pagnotta SM, Tala, Fan JJ, Russo MV, Lee SB, et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature. 2018;553(7687):222-7. 42. Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, et al. Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene. 2014;533(1):389-97. 43. Quant EC, Wen PY. Novel medical therapeutics in glioblastomas, including targeted molecular therapies, current and future clinical trials. Neuroimaging clinics of North America. 2010;20(3):425-48.
89
44. Marko NF, Weil RJ. The molecular biology of WHO grade I astrocytomas. Neuro-oncology. 2012;14(12):1424-31. 45. Mazloom A, Hodges JC, Teh BS, Chintagumpala M, Paulino AC. Outcome of patients with pilocytic astrocytoma and leptomeningeal dissemination. International journal of radiation oncology, biology, physics. 2012;84(2):350-4. 46. Ishkanian A, Laperriere NJ, Xu W, Millar BA, Payne D, Mason W, et al. Upfront observation versus radiation for adult pilocytic astrocytoma. Cancer. 2011;117(17):4070-9. 47. Jain A, Amin AG, Jain P, Burger P, Jallo GI, Lim M, et al. Subependymoma: clinical features and surgical outcomes. Neurological research. 2012;34(7):677-84. 48. Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, et al. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer cell. 2015;27(5):728-43. 49. Gupta A, Dwivedi T. A Simplified Overview of World Health Organization Classification Update of Central Nervous System Tumors 2016. J Neurosci Rural Pract. 2017;8(4):629-41. 50. Kebudi R, Cakir FB. Management of diffuse pontine gliomas in children: recent developments. Paediatric drugs. 2013;15(5):351-62. 51. Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer treatment reviews. 2012;38(1):27-35. 52. Bartlett F, Kortmann R, Saran F. Medulloblastoma. Clinical oncology. 2013;25(1):36-45. 53. Ajeawung NF, Wang HY, Gould P, Kamnasaran D. Advances in molecular targets for the treatment of medulloblastomas. Clin Invest Med. 2012;35(5):E246. 54. Archer TC, Pomeroy SL. Medulloblastoma biology in the post-genomic era. Future Oncol. 2012;8(12):1597-604. 55. Shonka N, Brandes A, De Groot JF. Adult medulloblastoma, from spongioblastoma cerebelli to the present day: a review of treatment and the integration of molecular markers. Oncology (Williston Park). 2012;26(11):1083-91. 56. Sonabend AM, Ogden AT, Maier LM, Anderson DE, Canoll P, Bruce JN, et al. Medulloblasoma: challenges for effective immunotherapy. Journal of neuro-oncology. 2012;108(1):1-10. 57. Byrd T, Grossman RG, Ahmed N. Medulloblastoma-biology and microenvironment: a review. Pediatric hematology and oncology. 2012;29(6):495-506. 58. Kumar V, Kumar V, McGuire T, Coulter DW, Sharp JG, Mahato RI. Challenges and Recent Advances in Medulloblastoma Therapy. Trends Pharmacol Sci. 2017;38(12):1061-84. 59. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, et al. Medulloblastomics: the end of the beginning. Nature reviews Cancer. 2012;12(12):818-34. 60. Fathi AR, Roelcke U. Meningioma. Curr Neurol Neurosci Rep. 2013;13(4):337. 61. Vranic A, Peyre M, Kalamarides M. New insights into meningioma: from genetics to trials. Current opinion in oncology. 2012;24(6):660-5. 62. Pecina-Slaus N, Kafka A, Lechpammer M. Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling. Cancers (Basel). 2016;8(7). 63. National Institute for Health and Care Excellence. Brain tumours (primary) and brain metastases in adults: NICE; 2018 [Available from: https://www.nice.org.uk/guidance/ng99. 64. Cancer Council Australia, Clinical Oncological Society of Australia. Clinical Practice Guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas [online document available at: https://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/Clinical_Practice_Guidelines-Adult_Gliomas-AUG09.pdf accessed March 2018]. 2009. 65. Hamilton W, Kernick D. Clinical features of primary brain tumours: a case-control study using electronic primary care records. Br J Gen Pract. 2007;57(542):695-9. 66. Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, Fisher B, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of
90
the EORTC 26981/22981-NCIC CE3 phase III randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(16):2563-9. 67. Schmidt-Hansen M, Berendse S, Hamilton W. Symptomatic diagnosis of cancer of the brain and central nervous system in primary care: a systematic review. Fam Pract. 2015;32(6):618-23. 68. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, Group EGW. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25 Suppl 3:iii93-101. 69. Sepulveda-Sanchez JM, Munoz Langa J, Arraez MA, Fuster J, Hernandez Lain A, Reynes G, et al. SEOM clinical guideline of diagnosis and management of low-grade glioma (2017). Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2018;20(1):3-15. 70. Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18(6):e315-e29. 71. American Brain Tumor Association. Care of the adult patient with a brain tumor. AAAN Clinical Practice Guideline Series. 2014. 72. Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, et al. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer letters. 2016;375(2):263-73. 73. Bush NA, Butowski N. The Effect of Molecular Diagnostics on the Treatment of Glioma. Curr Oncol Rep. 2017;19(4):26. 74. Ludwig K, Kornblum HI. Molecular markers in glioma. Journal of neuro-oncology. 2017;134(3):505-12. 75. Bradley WG, Jr., Waluch V, Yadley RA, Wycoff RR. Comparison of CT and MR in 400 patients with suspected disease of the brain and cervical spinal cord. Radiology. 1984;152(3):695-702. 76. Smith AS, Weinstein MA, Modic MT, Pavlicek W, Rogers LR, Budd TG, et al. Magnetic resonance with marked T2-weighted images: improved demonstration of brain lesions, tumor, and edema. AJR American journal of roentgenology. 1985;145(5):949-55. 77. la Fougere C, Suchorska B, Bartenstein P, Kreth FW, Tonn JC. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro-oncology. 2011;13(8):806-19. 78. Glaudemans AW, Enting RH, Heesters MA, Dierckx RA, van Rheenen RW, Walenkamp AM, et al. Value of 11C-methionine PET in imaging brain tumours and metastases. European journal of nuclear medicine and molecular imaging. 2013;40(4):615-35. 79. Demetriades AK, Almeida AC, Bhangoo RS, Barrington SF. Applications of positron emission tomography in neuro-oncology: a clinical approach. Surgeon. 2014;12(3):148-57. 80. Villanueva-Meyer JE, Mabray MC, Cha S. Current Clinical Brain Tumor Imaging. Neurosurgery. 2017;81(3):397-415. 81. Zacher A, Kaulich K, Stepanow S, Wolter M, Kohrer K, Felsberg J, et al. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel. Brain Pathol. 2017;27(2):146-59. 82. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-74. 83. Chaudhry NS, Shah AH, Ferraro N, Snelling BM, Bregy A, Madhavan K, et al. Predictors of long-term survival in patients with glioblastoma multiforme: advancements from the last quarter century. Cancer investigation. 2013;31(5):287-308. 84. Weiler M, Wick W. Molecular predictors of outcome in low-grade glioma. Current opinion in neurology. 2012;25(6):767-73. 85. Zhao H, Wang S, Song C, Zha Y, Li L. The prognostic value of MGMT promoter status by pyrosequencing assay for glioblastoma patients' survival: a meta-analysis. World J Surg Oncol. 2016;14(1):261.
91
86. Binabaj MM, Bahrami A, ShahidSales S, Joodi M, Joudi Mashhad M, Hassanian SM, et al. The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials. J Cell Physiol. 2018;233(1):378-86. 87. Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, et al. The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro-oncology. 2014;16(9):1263-73. 88. Siegal T. Clinical impact of molecular biomarkers in gliomas. J Clin Neurosci. 2015;22(3):437-44. 89. Hu N, Cheng H, Zhang K, Jensen R. Evaluating the Prognostic Accuracy of Biomarkers for Glioblastoma Multiforme Using The Cancer Genome Atlas Data. Cancer Informatics. 2017;16:1176935117734844. 90. Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer cell. 2009;15(1):45-56. 91. Westphal M, Lamszus K. Circulating biomarkers for gliomas. Nature reviews Neurology. 2015;11(10):556-66. 92. Wan Y, Kim YT, Li N, Cho SK, Bachoo R, Ellington AD, et al. Surface-immobilized aptamers for cancer cell isolation and microscopic cytology. Cancer research. 2010;70(22):9371-80. 93. Australian Government Department of Health. Brain Cancer: Australian Brain Cancer Mission, online document 2017 [Available from: http://www.health.gov.au/internet/main/publishing.nsf/content/A091E85A15E4F93DCA25814E0005C8EE/$File/brain-cancer-fact-sheet-1.docx. 94. Rosenfeld MR, Pruitt AA. Management of malignant gliomas and primary CNS lymphoma: standard of care and future directions. Continuum (Minneap Minn). 2012;18(2):406-15. 95. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine. 2005;352(10):987-96. 96. Lara-Velazquez M, Al-Kharboosh R, Jeanneret S, Vazquez-Ramos C, Mahato D, Tavanaiepour D, et al. Advances in Brain Tumor Surgery for Glioblastoma in Adults. Brain Sci. 2017;7(12). 97. Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis. JAMA Oncol. 2016;2(11):1460-9. 98. Cancer Council Australia, Clinical Oncological Society of Australia. Clinical Practice Guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas. 2009. 99. Walker DA, Liu J, Kieran M, Jabado N, Picton S, Packer R, et al. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro-oncology. 2013;15(4):462-8. 100. Veeravagu A, Jiang B, Ludwig C, Chang SD, Black KL, Patil CG. Biopsy versus resection for the management of low-grade gliomas (Review). Cochrane Database Syst Rev. 2013(4):CD009319. 101. Jiang B, Chaichana K, Veeravagu A, Chang SD, Black KL, Patil CG. Biopsy versus resection for the management of low-grade gliomas. Cochrane Database Syst Rev. 2017;4:CD009319. 102. Hart MG, Grant R, Metcalfe SE. Biopsy versus resection for high grade glioma (Review). Cochrane Database Syst Rev. 2000 (rev. 2011). 103. Barone DG, Lawrie TA, Hart MG. Image guided surgery for the resection of brain tumours (Review). Cochrane Database Syst Rev. 2014;28(1):CD009685. 104. Jenkinson MD, Barone DG, Bryant A, Vale L, Bulbeck H, Lawrie TA, et al. Intraoperative imaging technology to maximise extent of resection for glioma. Cochrane Database Syst Rev. 2018;1:CD012788. 105. Magill ST, Han SJ, Li J, Berger MS. Resection of primary motor cortex tumors: feasibility and surgical outcomes. Journal of neurosurgery. 2017:1-12.
92
106. Ashraf O, Patel NV, Hanft S, Danish SF. Laser-Induced Thermal Therapy in Neuro-Oncology: A Review. World neurosurgery. 2018;112:166-77. 107. Wurth R, Barbieri F, Florio T. New molecules and old drugs as emerging approaches to selectively target human glioblastoma cancer stem cells. BioMed research international. 2014;2014:126586. 108. Darefsky AS, King JT, Jr., Dubrow R. Adult glioblastoma multiforme survival in the temozolomide era: a population-based analysis of Surveillance, Epidemiology, and End Results registries. Cancer. 2012;118(8):2163-72. 109. Hart MG, Garside R, Rogers G, Stein K, Grant R. Temozolomide for high grade glioma. Cochrane Database Syst Rev. 2013;Apr 30(4):CD007415. 110. Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK. MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma. Pediatric blood & cancer. 2007;48(4):403-7. 111. Narita Y. Chemotherapy of Diffuse Astrocytoma (WHO grade II) in Adults. Progress in neurological surgery. 2018;31:145-51. 112. Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Chemotherapy wafers for high grade glioma. Cochrane Database Syst Rev. 2011;16(3):CD007294. 113. Chowdhary SA, Ryken T, Newton HB. Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis. Journal of neuro-oncology. 2015;122(2):367-82. 114. Quon H, Abdulkarim B. Adjuvant treatment of anaplastic oligodendrogliomas and oligoastrocytomas (Review). Cochrane Database Syst Rev. 2008. 115. Kast RE, Boockvar JA, Bruning A, Cappello F, Chang WW, Cvek B, et al. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget. 2013;4(4):502-30. 116. Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M, et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro-oncology. 2012;14 Suppl 4:iv100-8. 117. Zhu JJ, Wong ET. Personalized medicine for glioblastoma: current challenges and future opportunities. Curr Mol Med. 2013;13(3):358-67. 118. Sarmiento JM, Venteicher AS, Patil CG. Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev. 2015(6):CD009229. 119. Shah JL, Li G, Shaffer JL, Azoulay MI, Gibbs IC, Nagpal S, et al. Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma. Neurosurgery. 2018;82(1):24-34. 120. Carlson JA, Reddy K, Gaspar LE, Ney D, Kavanagh BD, Damek D, et al. Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials. Journal of neuro-oncology. 2015;123(2):251-7. 121. Navarria P, Pessina F, Cozzi L, Ascolese AM, Lobefalo F, Stravato A, et al. Can advanced new radiation therapy technologies improve outcome of high grade glioma (HGG) patients? analysis of 3D-conformal radiotherapy (3DCRT) versus volumetric-modulated arc therapy (VMAT) in patients treated with surgery, concomitant and adjuvant chemo-radiotherapy. BMC cancer. 2016;16:362. 122. Navarria P, Pessina F, Tomatis S, Soffietti R, Grimaldi M, Lopci E, et al. Are three weeks hypofractionated radiation therapy (HFRT) comparable to six weeks for newly diagnosed glioblastoma patients? Results of a phase II study. Oncotarget. 2017;8(40):67696-708. 123. Barbarisi M, Romanelli P. The emerging role of stereotactic radiosurgery in the treatment of glioblastoma multiforme. Curr Radiopharm. 2012;5(4):292-9. 124. Hallemeier CL, Pollock BE, Schomberg PJ, Link MJ, Brown PD, Stafford SL. Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. International journal of radiation oncology, biology, physics. 2012;83(1):107-12.
93
125. Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(18):3048-53. 126. Navarria P, Pessina F, Cozzi L, Ascolese AM, De Rose F, Fogliata A, et al. Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection. Radiat Oncol. 2016;11:76. 127. Khan L, Soliman H, Sahgal A, Perry J, Xu W, Tsao MN. External beam radiation dose escalation for high grade glioma. Cochrane Database Syst Rev. 2016(8):CD011475. 128. Zhang I, Formenti SC, Knisely JPS. Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 1: Principles of Combined Treatment. Oncology (Williston Park). 2018;32(2):e28-e32. 129. Elaimy AL, Mackay AR, Lamoreaux WT, Demakas JJ, Fairbanks RK, Cooke BS, et al. Clinical outcomes of gamma knife radiosurgery in the salvage treatment of patients with recurrent high-grade glioma. World neurosurgery. 2013;80(6):872-8. 130. Patil CG, Pricola K, Sarmiento JM, Garg SK, Bryant A, Black KL. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev. 2017;9:CD006121. 131. Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012(4):CD003869. 132. Tsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018;1:CD003869. 133. Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro-oncology. 2010;12(2):116-21. 134. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA : the journal of the American Medical Association. 2017;318(23):2306-16. 135. Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD. Tumor-Treating Fields: A Fourth Modality in Cancer Treatment. Clin Cancer Res. 2018;24(2):266-75. 136. Zhu P, Zhu JJ. Tumor treating fields: a novel and effective therapy for glioblastoma: mechanism, efficacy, safety and future perspectives. Chin Clin Oncol. 2017;6(4):41. 137. Mehta M, Wen P, Nishikawa R, Reardon D, Peters K. Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Rev Oncol Hematol. 2017;111:60-5. 138. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers 2016 [Available from: https://www.nccn.org/professionals/physician_gls/default.aspx. 139. Paolillo M, Boselli C, Schinelli S. Glioblastoma under Siege: An Overview of Current Therapeutic Strategies. Brain Sci. 2018;8(1). 140. Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Annals of oncology : official journal of the European Society for Medical Oncology. 2009;20(9):1596-603. 141. Padfield E, Ellis HP, Kurian KM. Current Therapeutic Advances Targeting EGFR and EGFRvIII in Glioblastoma. Frontiers in oncology. 2015;5:5. 142. Fu P, He YS, Huang Q, Ding T, Cen YC, Zhao HY, et al. Bevacizumab treatment for newly diagnosed glioblastoma: Systematic review and meta-analysis of clinical trials. Mol Clin Oncol. 2016;4(5):833-8.
94
143. Gan HK, van den Bent M, Lassman AB, Reardon DA, Scott AM. Antibody-drug conjugates in glioblastoma therapy: the right drugs to the right cells. Nature reviews Clinical oncology. 2017;14(11):695-707. 144. Han CH, Batchelor TT. Isocitrate dehydrogenase mutation as a therapeutic target in gliomas. Chin Clin Oncol. 2017;6(3):33. 145. Xu T, Wang H, Huang X, Li W, Huang Q, Yan Y, et al. Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment. Translational oncology. 2018;11(3):609-18. 146. Bregy A, Wong TM, Shah AH, Goldberg JM, Komotar RJ. Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer treatment reviews. 2013;39(8):891-907. 147. Rolle CE, Sengupta S, Lesniak MS. Challenges in clinical design of immunotherapy trials for malignant glioma. Neurosurgery clinics of North America. 2010;21(1):201-14. 148. Bielamowicz K, Khawja S, Ahmed N. Adoptive cell therapies for glioblastoma. Frontiers in oncology. 2013;3:275. 149. Dunn-Pirio AM, Vlahovic G. Immunotherapy approaches in the treatment of malignant brain tumors. Cancer. 2017;123(5):734-50. 150. Platten M, Reardon DA. Concepts for Immunotherapies in Gliomas. Semin Neurol. 2018;38(1):62-72. 151. Huang J, Liu F, Liu Z, Tang H, Wu H, Gong Q, et al. Immune Checkpoint in Glioblastoma: Promising and Challenging. Front Pharmacol. 2017;8:242. 152. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res. 2016;4(2):124-35. 153. Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373-85. 154. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7(275):275ra22. 155. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. The New England journal of medicine. 2016;375(26):2561-9. 156. Bauman GS, Sneed PK, Wara WM, Stalpers LJ, Chang SM, McDermott MW, et al. Reirradiation of primary CNS tumors. International journal of radiation oncology, biology, physics. 1996;36(2):433-41. 157. Alphandery E. Glioblastoma Treatments: An Account of Recent Industrial Developments. Front Pharmacol. 2018;9:879. 158. Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: a review of the challenging road to the bedside. Journal of neurology, neurosurgery, and psychiatry. 2013;84(2):213-22. 159. Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro-oncology. 2015;17 Suppl 2:ii24-ii36. 160. Desjardins A, Sampson JH, Peters KB, Vlahovic G, Randazzo D, Threatt S, et al. Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination. Journal of Clinical Oncology. 2015;33(15_suppl):2068-. 161. Jiang H, Clise-Dwyer K, Ruisaard KE, Fan X, Tian W, Gumin J, et al. Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model. PloS one. 2014;9(5):e97407. 162. Tejada S, Alonso M, Patino A, Fueyo J, Gomez-Manzano C, Diez-Valle R. Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients. Neurosurgery. 2017.
95
163. Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med. 2018;10(422). 164. Ji N, Weng D, Liu C, Gu Z, Chen S, Guo Y, et al. Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma. Oncotarget. 2016;7(4):4369-78. 165. Jiang H, Rivera-Molina Y, Gomez-Manzano C, Clise-Dwyer K, Bover L, Vence LM, et al. Oncolytic Adenovirus and Tumor-Targeting Immune Modulatory Therapy Improve Autologous Cancer Vaccination. Cancer research. 2017;77(14):3894-907. 166. GuhaSarkar D, Su Q, Gao G, Sena-Esteves M. Systemic AAV9-IFNbeta gene delivery treats highly invasive glioblastoma. Neuro-oncology. 2016;18(11):1508-18. 167. Desjardins A, Gromeier M, Herndon JE, 2nd, Beaubier N, Bolognesi DP, Friedman AH, et al. Recurrent Glioblastoma Treated with Recombinant Poliovirus. The New England journal of medicine. 2018;379(2):150-61. 168. Mitchell LA, Lopez Espinoza F, Mendoza D, Kato Y, Inagaki A, Hiraoka K, et al. Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro-oncology. 2017;19(7):930-9. 169. Karim R, Palazzo C, Evrard B, Piel G. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art. J Control Release. 2016;227:23-37. 170. Hernandez-Pedro NY, Rangel-Lopez E, Magana-Maldonado R, de la Cruz VP, del Angel AS, Pineda B, et al. Application of nanoparticles on diagnosis and therapy in gliomas. BioMed research international. 2013;2013:351031. 171. Alexiou C, Arnold W, Klein RJ, Parak FG, Hulin P, Bergemann C, et al. Locoregional cancer treatment with magnetic drug targeting. Cancer research. 2000;60(23):6641-8. 172. Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29(4):487-96. 173. Chertok B, David AE, Huang Y, Yang VC. Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics. J Control Release. 2007;122(3):315-23. 174. Koo YE, Reddy GR, Bhojani M, Schneider R, Philbert MA, Rehemtulla A, et al. Brain cancer diagnosis and therapy with nanoplatforms. Advanced drug delivery reviews. 2006;58(14):1556-77. 175. Pourgholi F, Hajivalili M, Farhad JN, Kafil HS, Yousefi M. Nanoparticles: Novel vehicles in treatment of Glioblastoma. Biomed Pharmacother. 2016;77:98-107. 176. Kumari S, Ahsan SM, Kumar JM, Kondapi AK, Rao NM. Overcoming blood brain barrier with a dual purpose Temozolomide loaded Lactoferrin nanoparticles for combating glioma (SERP-17-12433). Sci Rep. 2017;7(1):6602. 177. Jin J, Bae KH, Yang H, Lee SJ, Kim H, Kim Y, et al. In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles. Bioconjug Chem. 2011;22(12):2568-72. 178. Cho DY, Lin SZ, Yang WK, Lee HC, Hsu DM, Lin HL, et al. Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant. 2013;22(4):731-9. 179. Wang X, Huang X, Yang Z, Gallego-Perez D, Ma J, Zhao X, et al. Targeted delivery of tumor suppressor microRNA-1 by transferrin-conjugated lipopolyplex nanoparticles to patient-derived glioblastoma stem cells. Curr Pharm Biotechnol. 2014;15(9):839-46. 180. Bago JR, Alfonso-Pecchio A, Okolie O, Dumitru R, Rinkenbaugh A, Baldwin AS, et al. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat Commun. 2016;7:10593. 181. Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW, et al. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology. 2010;255(2):415-25. 182. Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016;8(343):343re2.
96
183. Rodriguez A, Tatter SB, Debinski W. Neurosurgical Techniques for Disruption of the Blood-Brain Barrier for Glioblastoma Treatment. Pharmaceutics. 2015;7(3):175-87. 184. Zhao X, Chen R, Liu M, Feng J, Chen J, Hu K. Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy. Acta Pharm Sin B. 2017;7(5):541-53. 185. Gebler C, Lohoff T, Paszkowski-Rogacz M, Mircetic J, Chakraborty D, Camgoz A, et al. Inactivation of Cancer Mutations Utilizing CRISPR/Cas9. J Natl Cancer Inst. 2017;109(1). 186. van den Bent M, Gan HK, Lassman AB, Kumthekar P, Merrell R, Butowski N, et al. Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. Cancer chemotherapy and pharmacology. 2017;80(6):1209-17. 187. Rundle-Thiele D, Head R, Cosgrove L, Martin JH. Repurposing some older drugs that cross the blood-brain barrier and have potential anticancer activity to provide new treatment options for glioblastoma. Br J Clin Pharmacol. 2016;81(2):199-209. 188. Rodriguez GA, Shah AH, Gersey ZC, Shah SS, Bregy A, Komotar RJ, et al. Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma. Ther Adv Med Oncol. 2016;8(4):248-60. 189. Ogawa T, Sawada N, Iwasaki M, Budhathoki S, Hidaka A, Yamaji T, et al. Coffee and green tea consumption in relation to brain tumor risk in a Japanese population. International journal of cancer. 2016;139(12):2714-21. 190. Sremanakova J, Sowerbutts AM, Burden S. A systematic review of the use of ketogenic diets in adult patients with cancer. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2018. 191. Malkki H. Neuro-oncology: Exercise could help to counteract radiation damage in children with brain tumours. Nature reviews Neurology. 2016;12(10):555. 192. Muller C, Krauth KA, Gerss J, Rosenbaum D. Physical activity and health-related quality of life in pediatric cancer patients following a 4-week inpatient rehabilitation program. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2016;24(9):3793-802. 193. Piscione PJ, Bouffet E, Timmons B, Courneya KS, Tetzlaff D, Schneiderman JE, et al. Exercise training improves physical function and fitness in long-term paediatric brain tumour survivors treated with cranial irradiation. European journal of cancer (Oxford, England : 1990). 2017;80:63-72. 194. Riggs L, Piscione J, Laughlin S, Cunningham T, Timmons BW, Courneya KS, et al. Exercise training for neural recovery in a restricted sample of pediatric brain tumor survivors: a controlled clinical trial with crossover of training versus no training. Neuro-oncology. 2017;19(3):440-50. 195. Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev. 2015(11):Cd009464. 196. Long W, Yi Y, Chen S, Cao Q, Zhao W, Liu Q. Potential New Therapies for Pediatric Diffuse Intrinsic Pontine Glioma. Front Pharmacol. 2017;8:495. 197. Newton HB, Ruda R, Soffietti R. Ependymomas, neuronal and mixed neuronal-glial tumors, dysembroblastic neuroepithelial tumors, pleomorphic xanthoastrocytomas, and pilocytic astrocytomas. Handbook of clinical neurology. 2012;105:551-67. 198. Gupta K, Salunke P. Understanding Ependymoma Oncogenesis: an Update on Recent Molecular Advances and Current Perspectives. Mol Neurobiol. 2017;54(1):15-21. 199. Bautista F, Fioravantti V, de Rojas T, Carceller F, Madero L, Lassaletta A, et al. Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update. Cancer medicine. 2017;6(11):2606-24. 200. Walcott BP, Nahed BV, Brastianos PK, Loeffler JS. Radiation Treatment for WHO Grade II and III Meningiomas. Frontiers in oncology. 2013;3:227. 201. Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18(6):e315-e29.
97
202. Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017;14(2):307-20. 203. Chaskis C, Neyns B, Michotte A, De Ridder M, Everaert H. Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations. Surgical neurology. 2009;72(4):423-8. 204. de Wit MCY. Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. 2004. 205. Gerstner ER, McNamara MB, Norden AD, Lafrankie D, Wen PY. Effect of adding temozolomide to radiation therapy on the incidence of pseudo-progression. Journal of neuro-oncology. 2009;94(1):97-101. 206. Knudsen-Baas KM, Moen G, Fluge O, Storstein A. Pseudoprogression in high-grade glioma. Acta neurologica Scandinavica Supplementum. 2013(196):31-7. 207. Miranda A, Blanco-Prieto M, Sousa J, Pais A, Vitorino C. Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches. Int J Pharm. 2017;531(1):372-88.
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