Current Knowledge in Brain Cancer Research
The 2018 literature review provides a broad overview of the field of brain cancer research for people impacted by brain cancer and those interested in brain cancer research. This review will help to inform future strategic decision-making for Cure Brain Cancer Foundation and provides an update since the last review conducted in 2014. The following is a summary of the main themes discussed in the review. Click here to download a PDF of the full
Literature Review.
2018 Literature Review Lay Summary
Summary
The aim of the 2018
Literature Review is to provide a broad overview of the field of brain cancer
research for people impacted by brain cancer and those interested in brain
cancer research, including brain cancer scientists early in their careers. Additionally,
this review will help to inform future strategic decision-making for the Cure
Brain Cancer Foundation. You can download a full PDF copy of the 2018
Literature Review, including the full reference list, here.
Since the last
review was conducted in 2014 there has been a huge amount of research conducted
on all aspects of brain cancer with thousands of academic manuscripts
published. The 2018 Literature Review
includes high quality research and outlines key developments. This summary
outlines the main themes discussed in the review.
Risk factors
Every year around 1,750
new cases of brain cancer are diagnosed in Australia and 1,250 people die of
brain cancer. Although there is little known about the underlying cause of
brain cancer it is known that ionising radiation is a risk factor, and that
there is a higher incidence observed in men and with increasing age.
A family history of
glioma is rarely observed but, when present, is associated with a two-fold
increase in the risk of developing glioma. A recent study also found that
people with a history of respiratory allergies had a significantly lower glioma
risk compared to those without respiratory allergies.(1)
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. (2, 3)
Despite many studies into mobile phone
use and glioma risk the quality and quantity of the available evidence is poor.(4)
Molecular biology
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.(5)
The molecular causes of brain tumours
are highly variable between each patient and each brain tumour. However,
recently genome-wide molecular-association studies have revealed some of the
key common genetic alterations and epigenetic profiles associated with the
different types of gliomas. (6, 7)
Such developments led to the World Health Organization (WHO) restructuring of
the classification of tumours in May 2016.(8)
The new classification combines molecular biomarkers and histological features
in an integrated diagnosis.
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. The major signalling pathways involved in glioblastoma pathogenesis include the PI3K/AKT/mTOR, Ras/RAF/MEK/MAPK, Rb, p53, Wnt, TGFb, and UPR pathways. These pathways regulate cell proliferation, adhesion
and migration, invasion, angiogenesis, cell survival, and stemness. Numerous
other mutations or pathway aberrations have been associated with specific
tumour subsets and are detailed in the full 2018 Literature Review.
IDH1/2
mutations
IDH mutation is probably among the earliest genetic
aberrations that occur during glioma development. When mutated, the IDH1 and
IDH2 enzymes have significantly reduced activity and this leads to further
changes at the DNA level called hypermethylation. However, IDH mutation alone
is not sufficient for tumorigenesis. (9)
Mutations in IDH-1 and IDH-2 are also common in oligodendrogliomas.
PTEN mutations and deletions
PTEN acts as a tumour suppressor and mutations in this gene
are found in many cancers including prostate and breast cancer. Recent studies
have shown PTEN mutations occur in 7% of anaplastic but they are not found in
low-grade gliomas. New research also suggests that when PTEN is deleted it does
not promote tumour growth early in tumour development but is linked to heightened
invasiveness. (10) PTEN also regulates p53
protein levels.
Chromosome 1p/19q co-deletion
Loss of heterozygosity or co-deletion of chromosome 1p and 19q
is common in oligodendroglial tumours and is associated with both favourable
treatment response to first-line chemotherapy and improved survival. (10) 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. (11)
Deletions of chromosome 1p and 19q are rare in GBM tumours, occurring in less
than 10% of cases.
Epigenetic
changes have been linked with all cancer types and are now recognised to be as important to cancer formation as gene mutations. For example in GBM tumours, MGMT (a gene encoding a DNA repair enzyme) is often silenced by epigenetic changes. When DNA repair is shut down tumour development is accelerated. Approximately 40–50% of primary GBM tumours and 70% of secondary GBM tumours display epigenetic MGMT silencing. (11, 12)
MicroRNAs
(miRNAs) are small
lengths of RNA involved in the regulation of gene expression. Mounting evidence
suggests that miRNA levels are critical in development of tumours.
Brain tumour
stem cells probably drive tumour progression because of their self-renewal capacity and limitless proliferative potential. Studies suggest that stem cells are controlled by a particular microenvironment known as a "niche" and that the abundance of niches increases significantly as tumour grade increases. Recent findings show that cancer stem cells may contribute to the resistance of malignant gliomas to chemotherapy and radiotherapy.
Angiogenesis is the process of new blood vessel
formation and is a critical process in the growth of many solid tumours
including glioblastoma. Tumour cells release pro-angiogenic factors that
promote angiogenesis.
Detection, diagnosis & prognosis
Symptoms
Brain
tumour symptoms depend on a large number of variables including the size,
location and rate of growth of the tumour. Patients can have varied
symptoms when presenting with a primary brain tumour including: headache,
nausea/vomiting, cognition changes, personality changes, gait imbalance,
urinary incontinence, hemiparesis, aphasia, hemi-neglect, visual field defect,
and seizures.
A large systematic review of 159,938 patients found that
most symptoms are not a very accurate way to predict that people have a brain
tumour, with the exception of new-onset
epilepsy. (13) 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) were even less predictive of CNS cancer. (13)
Diagnosis
There are more than 120 types of brain and central
nervous system (CNS) tumours. Clinical
Practice Guidelines in Australia for the diagnosis and management of gliomas require updating
(published in 2009). (14) Current international
guidelines are also lacking, although the National Institute for Health and
Care Excellence in the UK is currently developing a Clinical Guideline for Brain
tumours (primary) and brain metastases in adults, which is due for publication
in July 2018.
The new 2016 WHO classification defines tumours 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 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.
Imaging
The aim of imaging
brain tumours is to diagnose, localise and characterise them. Imaging
technology is rapidly evolving with continual developments and improvements in Computed Tomography (CT), Magnetic Resonance Imaging (MRI),
Positron Emission Tomography (PET),
and also nuclear medicine techniques. In fact the progress is so rapid that it
makes it difficult to ensure that the evidence-based guidelines in radiology
are up to date. (14) MRI has now largely
replaced CT as an
imaging technique. MRI has the benefit of being more specific and sensitive
than CT, particularly in the context of evaluating non-enhancing lesions. More
recently, the use of molecular imaging with PET has come into use. PET can more fully characterise
brain tumours by investigating metabolic processes such as DNA synthesis or
enzyme activity, receptor binding, oxygen metabolism, as well as blood
flow. Diffusion-weighted
imaging (DWI) also has significant value in the assessment of brain
tumours. (15)
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.
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. (16)
Prognosis
The prognosis of a
patient with glioblastoma rests on a number of factors including:
Age
Pre-operative
Karnofsky Performance Status (KPS) score (>70)
Tumour
size, location and resection (extent of removal)
Combined
radiotherapy and chemotherapy
Post-operative
complications
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).
Biomarkers may also provide information about prognosis, for example in
GBM patients, positive MGMT promoter status and IDH-mutation positive tumours have
been associated with increased survival. (17)
While the use of
biomarkers in the diagnosis and prognosis of CNS tumours is increasing, the
current evidence for their utility in predicting overall survival is limited.
Nevertheless, if other clinical risk factors, such as age, are incorporated
this can greatly improve the prognostic performance. In the future, combining genomic data with and imaging
data may also improve the accuracy of the diagnosis and the prognostic
performance.
Treatment
Approaches to
tumour treatment vary significantly from patient to patient and depend on a
large number of factors including histological and biomarker findings, grade and
location of the tumour, and the age and medical condition of the patient. The
standard-of-care for treatment of glioma includes surgical resection, radiation
and chemotherapy, either alone or in combination.
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, it is likely that in the future a combination of molecular
therapies will be necessary. Predictive DNA sequencing followed by targeted
therapy will support the implementation of precision
medicine in neuro-oncology.
Surgery
Current surgical
techniques for tumour resection include cortical
mapping of the brain, fluorescence-guided
surgery, laser interstitial thermal
therapy, and intraoperative mass
spectrometry.
Surgery is an important modality for improving prognosis in
patients with gliomas. (18)
A recent 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. (19)
Australian clinical
practice guidelines provide clear evidence-based guidelines on the surgical
treatment of different grades of glioma. The 2014 ESMO Clinical
Practice Guidelines advise it
may be beneficial to attempt maximal
tumour resection provided that neurological function is not compromised by
the extent of resection but it is noted that 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. (20)
An updated Cochrane review examining the benefits of image-guided surgery for the resection
of brain tumours was published in 2018. (21) This study included trials of 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. Results showed that in participants with high grade
glioma iMRI and 5-ALA may be of benefit in maximising the extent of resection. However,
the available evidence is of low to very low quality, the short- and long-term
neurological effects are uncertain, and effects on overall survival,
progression-free survival, and quality of life remain unclear. (21)
Laser interstitial
thermal therapy (LITT) and Optical Coherence Tomography (OCT) are relatively
new emerging treatments.
There is evidence
that centralised care and high volume units with skilled teams of health
professionals (hospitals that specialise in neuro-oncology) improve patient
outcomes.
Radiation and
chemotherapy
The current standard of care for the medical
management of newly diagnosed glioblastoma following resection includes the addition of temozolomide (TMZ) to radiation
therapy. However, most tumours eventually develop resistance to TMZ and there is no standard chemotherapy for
recurrent or progressive glioblastoma because of unfavourable outcomes with
currently available cytotoxic therapies. 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. Hypofractionated-intensity modulated radiotherapy (IMRT) and volumetric-modulated arc
therapy (VMAT) have shown promising
results in clinical trials when used in GBM patients in combination with
chemotherapy.(22-24)
Carmustine
wafers
Carmustine wafers (wafers
that are impregnated with chemotherapy agents) are inserted
directly into the tumour cavity at the time of resection but despite positive
improvements in median survival for patients with newly diagnosed high-grade
glioma, uptake of this treatment option has been poor.(25) This has mainly been due to concern
regarding adverse effects (including cerebrospinal fluid leakage and
intracranial hypertension) and challenges in interpretation of imaging findings
after wafer placement. (25, 26)
Drug
repurposing
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. (27)
Coordinated Undermining of Survival Paths (CUSP9) is a nine adjuvant drug
regimen (containing aprepitant, artesunate, auranofin, captopril, copper
gluconate, disulfiram, ketoconazole, nelfinavir, and sertraline) and a Phase I proof-of-concept clinical trial
is currently underway (NCT02770378).
Targeted
chemotherapy
As more is known
about the molecular classification of a tumour so too can chemotherapy be more targeted to specific tumour types. For
example, in GBM patients MGMT promoter methylation is correlated with reduced
resistance to the chemotherapy drug TMZ. In patients with anaplastic
oligodendroglial tumours there was only a survival benefit in those with the
1p/19q codeletion when treated with radiotherapy plus PCV (procarbazine,
lomustine, and vincristine). Routine tumour testing for 1p/19q and MGMT for GBM
patients is under investigation. (20, 28,
29)
Tumour-treating
fields
Tumour-treating
fields (TTFields or OptuneTM) deliver low-intensity,
intermediate-frequency, alternating electric fields to inhibit tumour growth via
a specialized helmet. In October 2015 TTFields in combination with TMZ for the
treatment of adults with newly diagnosed glioblastoma was approved by the US
Food and Drug Administration (FDA) for treatment of recurrent glioblastoma as a monotherapy after surgical and radiation options have been exhausted. TTFields has been called a “fourth cancer treatment modality,” after surgery, radiotherapy, and pharmacotherapy.
Immunotherapy
The past five years
have seen a sharp increase 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. Peptide vaccines, dendritic cell vaccines, and
immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) have demonstrated
improved overall survival for certain groups of patients with glioblastoma in
clinical Phase II/III trials. Currently, at least three immunotherapies are in Phase
III clinical trials.
Immune
checkpoint inhibitors
Immune checkpoint
inhibitors block proteins on the surface of immune cells and sometimes cancer
cells. Normally these surface proteins are important to keep immune responses
in check and prevent the immune system from being over-active. Immune checkpoint inhibitors work by blocking these
proteins and enabling immune cells such as T-cells to target cancer cells and
destroy them more effectively. Checkpoint proteins include PD-1/PD-L1 and
CTLA-4/B7-1/B7-2.
Vaccines
There have been a
number of vaccine trials in GBM patients. This is an emerging area of research
and treatment. The HSPPC-96 Phase II trial and the IMA-950 Phase I trial
(against multiple self-antigens) both showed safe and immunogenic results.
(30)
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. (26)
Personalised medicine
Genome sequencing has led to the new area of personalised medicine (also called precision medicine). Personalised medicine uses the data gathered from DNA sequencing the individual’s genome and/or brain tumour tissue to customise treatment to each individual. Molecular classification of each individual tumour to identify markers that define these subsets and to predict response to chemotherapeutic agents is an emerging area still undergoing development in glioblastoma treatment.
Emerging therapies
There are a number of new therapies in the research
pipeline or early phase clinical trials. These include suicide gene therapy, oncolytic
viruses and combined oncolytic and
immunotherapy.
Nanoparticles
are tiny microscopic particles that are between 1-100nanometers in diameter
(about one thousand time smaller than the width of a strand of hair).
Nanoparticles have properties
that help overcome the problems with getting treatments across the blood–brain barrier (BBB). Such
particles may provide a new option for glioma-targeted drug delivery.
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.
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. (31)This method delivers burst-tone ultrasound
energy in the presence of microbubbles.
(31)
Summary
Brain cancer remains
difficult to treat, although new therapeutic options are in the pipeline and
research activity in this area has shown exponential growth. There are a number
of difficulties in overcoming the natural barriers to get adequate access to the
tumour surgically, neurologically and medically. Recent advances in direct
delivery to the tumour, immunotherapy, genomics, and nanotechnology all stand
out as promising new treatment strategies. However, although promising many
require further research and clinical investigation before they become
available to all patients.
Click here to download a PDF of our full literature review
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