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2014 Literature Review

The descriptive literature review provides a high-level overview of new strategies, developments and milestones in brain tumour research, and provides a basis for future, strategic decision making for the Cure Brain Cancer Foundation. The following is a summary of the main themes discussed in the review. Click here to download a PDF of the full Literature Review. 

Aetiology

There is little known about the underlying cause of brain cancer. The only established risk factor is ionising radiation, and a higher incidence is observed with increasing age, and in men. There is no conclusive link between an increased risk of brain cancer and exposure to cell phones, other types of electromagnetic fields, head injury, foods containing N-nitroso compounds, aspartame, occupational risk factors, pesticides, or season of birth. Interestingly, glioma risk is slightly reduced in people with asthma, eczema and hay fever perhaps reflecting heightened immune surveillance of the brain.

Molecular biology 

One characteristic of all cancer cells is the presence of multiple changes at the molecular or DNA level. These include gene mutations and epigenetic changes (changes to gene expression that are not due to changes to genetic sequences). The molecular causes of brain tumours are highly variable between each patient and each brain tumour. Many of the alterations activate or inactivate pathways that control the growth and proliferation of tumour cells.

The most common pathways affected in primary glioblastoma (GBM) are: the p53 pathway, the RB1 pathway, the MAPK pathway, the P13K pathway. For secondary glioblastoma the most frequent pathways and genetic alterations include: TP53 mutation and/or loss of chromosome 17p, IDH1 and IDH2 mutations, loss of chromosomes 1p, 9p, 19q, 10q alone or in combination, RB1 pathway aberrations, and PTEN mutations.

These pathways are involved in cellular processes including:

  • apoptosis (cellular suicide)
  • angiogenesis (blood vessel formation)
  • DNA repair
  • cellular metabolism
  • oxidative stress
  • stem cell proliferation, survival and differentiation.  
  • cell migration, survival and tumour invasion 
  • enzyme activity 

Epigenetic changes have been linked with all cancer types and are now recognised to be as important to cancer formation as are gene mutations. 

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. 

Numerous other mutations or pathway aberrations have been found associated with specific tumour subsets and are detailed in the full review. 

Detection, diagnosis & prognosis

Brain tumour symptoms depend on the tumour’s size, location and rate of growth. Common symptoms include: headache nausea/vomiting, cognition (thinking) changes, personality changes, trouble walking, urinary incontinence, paralysis on one side of the body, problems with speech or vision, and seizures. But the likelihood that any of these symptoms is due to a brain tumour is very low. For example, 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.

The aim of imaging brain tumours is to diagnose, localise and characterise them.  Magnetic Resonance Imaging (MRI) has largely replaced Computed Tomography (CT) as an imaging technique. More recently, the use of molecular imaging with Positron Emission Tomography (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. 

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

Treatment

Approaches to tumour treatment vary by patient and tumour and are based on the histological finding, grade of the tumour, age and medical condition of the patient. 

The current standard of care for patients with newly diagnosed glioblastoma includes maximum safe tumour resection followed by a six week course of radiotherapy with concomitant systemic therapy using the alkylating agent temozolomide (TMZ) and followed by six months of adjuvant TMZ.

Surgery

Australian clinical practice guidelines provide clear evidence-based guidelines on the surgical treatment of different grades of glioma. 

There is some evidence that image-guided surgery may increase the proportion of patients with high-grade glioma that have a complete tumour resection. Intra-operative MRI (iMRI) is an emerging technique that reduces inaccuracies resulting from intraoperative brain movement that may occur during traditional surgical methods.

New surgical techniques involve using fluorescently-labelled markers to highlight the tumour and differentiate it from healthy brain tissue; surgery is carried out under fluorescence. 

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.

Medical Therapy

Improved knowledge of the molecular biology of brain tumours has led to the development of new potential therapeutic targets. A number of these therapies are now undergoing clinical trial; the majority of which are focused on:

  • identification of mechanisms to overcome TMZ resistance 
  • development of molecular targeted and anti-angiogenic agents (agents that prevent the development of new blood vessels)
  • immunotherapy 
  • drug combination  

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 wafers that are impregnated with chemotherapy agents and inserted directly into the cavity at the time of resection improve survival without an increased incidence of adverse events over placebo wafers when used for primary disease therapy. In recurrent disease, the wafers do not appear to confer any additional benefit.

Drug repurposing involves using drugs not traditionally used to treat brain tumours that have a robust history of being well-tolerated and are already marketed and used for other diseases. The International Initiative for Accelerated Improvement of Glioblastoma Care has proposed that a nine adjuvant drug regimen (Coordinated Undermining of Survival Paths; CUSP9) is added to low dose TMZ in patients with recurrent disease after primary treatment with the Stupp Protocol. 

Radiotherapy

Up 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.

Image-guided radiotherapy enables a precise radiation dose delivery and can reduce treatment time in glioblastoma and toxicity. Preservation of neurocognitive function may also be improved. A recent review recommended that future prospective trials for primary brain tumours or brain metastasis should include image-guided radiotherapy to assess its efficacy to impact on patient quality of life. 

Stereotactic radiosurgery is a relatively new treatment option for glioblastoma. High-energy beams are accurately focussed on the tumour.  Radiosurgery has the advantage of being non-invasive and can be performed as an outpatient procedure. Fractionated stereotactic radiotherapy allows precise treatment delivery while decreasing the dose to surrounding critical structures, reducing toxicity associated with stereotactic radiotherapy.

New therapies

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. A variety of vaccination approaches are in various stages of clinical development based on encouraging, albeit preliminary, evidence of therapeutic benefit from clinical trials. 

Gene therapy is defined as the targeted transfer of genetic material into tumour cells for therapeutic purposes. It has the ability to target invasive tumour cells that are resistant to conventional therapy. Although gene therapy has shown promise in preclinical applications, it has not met clinical expectations due to various impediments related to the nature of brain tumours and their location within the blood brain barrier. 

Another emerging area is the use of nanoparticles, which have been studied as a method to overcome the problems with getting treatments across the blood–brain barrier. Such particles may provide a new method for glioma-targeted drug delivery.

Targeting cancer stem cells has emerged as another treatment option. Stem cells have a multipotent function, have self-renewal potential and resistance to chemotherapy and radiotherapy. 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.

Genome sequencing has led to the advent of personalised medicine (also called precision medicine). Precision medicine uses the data gathered from genome sequencing to predict disease development or to tailor treatment to an individual. Molecular classification of each individual tumour to identify markers that define these subsets and to predict response to chemotherapeutic agents is an emerging development area in glioblastoma treatment.

Summary

Glioblastoma remains a difficult cancer to treat, although therapeutic options have been improving. Optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment.

Click here to download a PDF of the full Literature Review.

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