Associate editor: M. PanagiotidisGlioblastoma multiforme: Pathogenesis and treatment
Introduction
Each year, about 5–6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs) (Schwartzbaum et al., 2006, Stupp, Tonn, Brada and Pentheroudakis, 2010). Gliomas, the most common group of primary brain tumours, include astrocytomas, oligodendrogliomas and ependymomas. According to World Health Organization (WHO) malignant gliomas are subcategorized into grade III/IV tumors such as anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma and anaplastic ependymomas, as well as grade IV/IV tumors, as glioblastoma multiforme (GBM). The WHO grade is assigned based on certain pathological features, such as nuclear atypia, mitotic activity, vascular proliferation, necrosis, proliferative potential and features clinical course and treatment outcome (Louis et al., 2007). Its incidence in the United States is estimated around 3:100,000 while more than 10,000 cases are diagnosed annually. It constitutes 45.2% of all malignant central nervous system (CNS) tumors, 80% of all primary malignant CNS tumors and approximately 54.4% of all malignant gliomas. Mean age at diagnosis is 64 years and it is 1.5 times more common in men than women and 2 times more common in whites compared to blacks (Ostrom et al., 2013). The incidence has increased slightly over the past 20 years mostly due to improved radiologic diagnosis and especially in elderly (Fisher et al., 2007). In terms of treatment, grade III tumors and GBM are grouped together and treated similarly.
Clinically, patients with GBM may present with headaches, focal neurologic deficits, confusion, memory loss, personality changes or with seizures. Diagnosis and treatment response is suggested by magnetic resonance imaging (MRI) and the use of adjunct technology such as functional MRI, diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI, perfusion imaging, proton magnetic resonance spectroscopy and positron-emission tomography (Wen & Kesari, 2008).
Etiologically, there are known linked risk factors that lead to development of GBM Environmental risk factors include primarily exposure to therapeutic ionizing radiation and factors such as vinyl chloride or pesticides, smoking, petroleum refining or production work and employment in synthetic rubber manufacturing (Wrensch et al., 2002). Additional factors such as exposure to residential electromagnetic fields, formaldehyde, diagnostic irradiation and cell phones have not been proven to lead to GBM. However, regarding cell phone irradiation, a metanalysis released in 2007 did show increased incidence among people who used cell phones for at least 10 years and especially those who had mostly unilateral exposure (Hardell et al., 2007).
Currently, maximal surgical resection plus radiotherapy plus concomitant and adjuvant temozolomide or carmustin wafers (Gliadel) is the standard of care in patients younger than 70 years old with newly diagnosed GBM. However, recurrence seems to be the rule despite standard care. Lately, attention has been given to understand the initial molecular pathogenesis of these tumors including alterations in cellular signal transduction pathways, the occurrence of resistance to therapy and to find methods to penetrate easier the natural blood-brain barrier (BBB). Despite these efforts to treat however, it remains an incurable disease and the prognosis falls in a poor survival range of 12–15 months (median 14.6 months) and a mean survival rate of only 3.3% at 2 years and 1.2% at 3 years (Scott et al., 1998, Stupp et al., 2005).
Glioma stem cells contribute to resistance to standard radiotherapy via preferential activation of DNA-damage-response pathways; and to standard chemotherapy via O6-methylguanine-DNA methyltransferase (MGMT), the inhibition of apoptosis and the up-regulation of multidrug resistance genes (Dean et al., 2005). Thus, current efforts are directed towards personalized treatment through blocking prime signaling pathways in gliomagenesis, surpassing acquired resistance and by penetration of BBB. In this article we review the current concepts as well as emerging advances in the treatment of GBM with an emphasis on chemotherapy and targeted agents.
Section snippets
Pathogenesis
The ongoing research on the pathogenesis of malignant gliomas has given opportunities for newer therapies to evolve as well as promises for better control of the disease. Efforts are given to understand the development of tumor resistance (Dean et al., 2005, Furnari et al., 2007).
A small subgroup (about 5%) of patients with gliomas, is associated with certain hereditary syndromes (Farrell & Plotkin, 2007) (Table 1). All other patients with gliomas represent sporadic cases. An important aspect
Treatment
Currently, the standard approach in managing GBM includes consideration of maximum surgical resection -considering that the entire tumor cannot be removed because GBM infiltrates surrounding tissue- radiation therapy (RT) and medical management/chemotherapy. It also includes symptomatic treatment of seizures, cerebral edema, infections, depression, cognitive dysfunction, fatigue and venous thromboembolism (Wen et al., 2006a). However, the analysis of symptom palliation is not in the scope of
Conclusion
Research in GBM treatment is ongoing, vast, and rapidly evolving. However, even all this data and progression of molecular science it has not been able to battle effectively this tumor. No matter how many different targets are discovered and molecules to aim them are enginered, the end result is that we have made only a little progress forward in improving overall survival. However, as is seen in this review, every step in the way, new lessons drive us forward and small details help us bypass
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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