2018 Literature Review

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)

Gene panels and DNA-methylation profiling 

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 Optune^TM) 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)

Salvage therapies

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