Brain tumours: a major challenge

Primary brain tumours remain a significant challenge for physicians. They represent a life-changing event for patients and families. Glioblastoma (GBM) is the most common primary brain malignancy, accounting for 45.6% of all cases. The incidence rate is 3.19 per 100 000 and the median age of diagnosis is 64 years.¹ It is responsible for 2.5% of all cancer deaths and is the third highest causes of death from cancer in the 15-34 year age bracket.²

Approximately 450 patients are diagnosed with primary brain tumours in the Republic of Ireland every year. Little is known about the aetiology of brain tumours. To date, the only confirmed environmental risk factor is exposure to ionizing radiation.³ Other environmental risk factors, including vinyl chloride, pesticides, smoking, petroleum refining and synthetic rubber manufacturing, have been loosely associated with their development. Rates appear to be higher in more developed countries and are slightly more common in men (1.6:1).^4,5 Some familial syndromes, such as neurofibromatosis 1 and 2, tuberous sclerosis, Li-Fraumeni syndrome, retinoblastoma and Turcot syndrome, are also known to have an association with the development of glioma, but these account for less than 1% of all cases.⁶

Headache is the most common presenting complaint, especially early morning headache with associated vomiting. New neurological deficits should always prompt further investigation. Seizures account for 25% of presenting complaints and may occur as a later symptom in as many as 50% of cases.^7,8 A first seizure episode should be investigated with neuroimaging. This presentation is classically associated with a low grade glioma.

Unfortunately, there is no universal screening tool available to detect gliomas. Diagnosis can be quite challenging as the presenting symptoms are often non-specific. These can vary from personality changes, memory difficulties and sleep disturbance. MRI brain with and without contrast remains the gold standard for investigation.

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Treatment

There are two main goals of surgery: to obtain a histopathological diagnosis and molecular profile, the second is to achieve the maximum possible surgical resection while preserving neurological function. The extent of resection (EOR) plays a major role as an independent, modifiable factor associated with improved overall and progression-free survival.⁹ To reach this objective, different technologies and surgical techniques have been introduced in neuro-oncology surgery, including awake craniotomy, intraoperative 5-ALA fluorescence, functional neuronavigation systems, ultrasound surgery, intraoperative MRI scanning, and intraoperative cortical and subcortical mapping techniques.

Following surgical resection, external beam radiotherapy plays a central role in the treatment of GBM. A dose of 60Gy of radiation is delivered in 30 fractions of 2Gy to the involved area as well as up to 3cm of the margin in order to treat the infiltrating tumour. In older patients with a poorer functional status the dose can be administered in fewer fractions.

The addition of temozolomide, a DNA alkylating agent, to the treatment protocol also plays an important role in treating GBM. In 2005, Stupp et al showed that the adjuvant administration of concomitant temozolomide and radiotherapy, followed by six cycles of temozolomide, conferred a 2.5 month survival benefit over adjuvant radiotherapy alone.¹⁰ In addition, GBMs which were found to have methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promotor sequence have been shown to provide a survival benefit in patients treated with adjuvant radiation therapy and temozolomide.¹¹

More recently, the application of alternating electric fields, known as tumour-treating fields, has been shown to interfere with cellular replication in cancer cells. In the EF-14 trial, the application of tumour-treating fields has been shown to improve median overall survival to 20.5 months when added to the standard treatment protocol in recurrent GBM.¹² It is also associated with an improvement in quality of life and a lower incidence of serious adverse effects. However this treatment is very costly to administer, limiting its availability. The primary adverse effect associated with tumour-treating fields is skin irritation from the array, which is typically managed by repositioning the array and applying topical treatments to the affected area.¹³

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Prognosis

Despite extensive research, the prognosis associated with high grade gliomas in adults remains poor. There is also significant morbidity associated with LGG. Historically, many LGGs were managed expectantly because of their ‘indolent course’. However current evidence supports active management with surgical resection, +/- radiation and chemotherapy as there is a propensity for malignant transformation.¹⁴

A number of genetic markers are commonly assessed in the management of gliomas. These include IDH/ATRX and 1p/19q, which predominantly occur in astrocytomas and oligodendrogliomas respectively. As discussed above. MGMT methylation is an important prognostic factor in high grade gliomas.

The presence of IDH in a high grade lesion indicates progression from a low grade glioma as opposed to the de novo formation of a GBM. The addition of these genetic markers plays a critical role in identifying patients who will have the greatest prognostic benefit from adjuvant treatment.¹⁵

In 1980 the median survival of a GBM was eight months. Presently, the median survival is 14.6 months with a five-year survival rate of only 5.1%, despite significant advances in our understanding and treatment of the disease.

The most favourable prognostic factors are a younger age at diagnosis (50 years or younger), a Karnofsky performance factor of greater than 70 points and tumours located in a non-eloquent part of the brain.¹⁶

Future directions

Novel treatment strategies are under development with the aim of selectively targeting GBM cells. These include intratumoural gene therapy, which uses replicating retroviral gene transfer to either destroy tumour cells directly or activate the immune system against the tumour. Other approaches involve the use of monoclonal antibodies to target specific signalling receptors involved in GBM.¹⁷

Brain tumours can affect patients of all ages. Detection can be quite difficult due to a combination of non-specific presenting symptoms and a lack of effective screening tools. Further research in this area is necessary to enhance our understanding of the molecular microenvironment of many brain tumours and thereby improve overall survival and quality of life of our patients. 

References

1. Ostrom QT et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 2014;16(Suppl 4):iv1–iv63. doi: 10.1093/neuonc/nou223
2. Salcman M. Epidemiology and factors affecting survival. In: In malignant cerebral Glioma. Neurosurgical topic series. Apuzzo MLJ, editor. Ill. Park Ridge: American Association of Neurological Surgeons 1990. pp. 95-110
3. Ellor SV, Pagano-Young TA, Avgeropoulos NG. Glioblastoma: Background, standard treatment paradigms, and supportive care considerations. J Law Med Ethics 2014;42:171-182. doi: 10.1111/jlme.12133
4. Inskip PD et al. Cellular-telephone use and brain tumors. N Engl J Med. 2001;344:79-79
5. Bondy ML et al. Brain tumor epidemiology:consensus from the brain tumor epidemiology consortium. Cancer. 2008;113:1953-1953
6. Ellor SV, Pagano-Young TA, Avgeropoulos NG. Glioblastoma: Background, standard treatment paradigms, and supportive care considerations. J Law Med Ethics 2014;42:171–182. doi: 10.1111/jlme.12133
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8. Schiff D et al. Medical management of brain tumors and the sequelae of treatment. Neuro-Oncology 2015;17:488-504
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10. Stupp R et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005 Mar 10;352(10):987-96
11. Hegi ME et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352:997-1003
12. Kanner AA et al. EF-11 Investigators. Tumor treating fields (TTFields) in recurrent GBM. An updated subgroup analysis of the phase III data (abstract). Neuro Oncol 2013;15(suppl):3iii114
13. Ram Z, Gutin PH, Stupp R. Subgroup and quality of life analyses of the phase III clinical trial of NovoTTF-100A versus best standard chemotherapy for recurrent glioblastoma. Neuro Oncol 2010;12:48-49
14. Schiff D, Brown PD, Giannini C. Outcome in adult low-grade glioma: the impact of prognostic factors and treatment. Neurology. 2007;69:1366-1373
15. Cohen AL, Colman H. Glioma biology and molecular markers. Cancer Treat Res 2015;163:15-30
16. Theeler BJ, Gilbert MR. Advances in the treatment of newly diagnosed glioblastoma. BMC Medicine 2015;13, article 293 doi: 10.1186/s12916-015-0536-8
17. Alifieris C, Trafalis DT Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 2015 152:63-82