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Glioblastoma Multiforme

Brain tumors are uncontrolled and abnormal cell growth in the brain involving the central nervous system (CNS) causing life-threatening complications. The consequential damage to the brain becomes lethal. According to the WHO-IARC reports, the highest age of standardized annual incidence of CNS  or brain cancers in 2020 is from the U.S.A.  European countries such as Norway, U.K., and Ireland, as well as middle-east countries such as Turkey and Iran also show high figures. Brain tumors may either be primary (one that starts in the brain) or secondary (one that starts in other parts of the body and metastasizes to the brain). Primary tumors may be classified as glial tumors or gliomas (composed of glial cells) and non-glial tumors (developed on or in the structures of the brain, including nerves, blood vessels, and glands). About 80% of malignant brain tumors may be categorized as gliomas. The higher grade or grade IV glioma, also called glioblastoma, is one of the most lethal cancers in adults. There is a comprehensive report of 2020 from the global observatory of the WHO stating, that age-standardized incidence and mortality of 2.4 and 2.0 respectively in 1,00,000 population in the South East Asian countries including India in perspective of brain/CNS cancers, which is way less than the global incidence of 3.5 and 2.8 in 1,00,000, respectively population. Only two to three out of 1,00,000 individuals account for less than 2% of all diagnosed malignancies.

Glioblastoma, also called glioblastoma multiforme (GBM), and other malignant gliomas are highly invasive, infiltrating the surrounding brain parenchyma, yet they are typically confined to the central nervous system (CNS) and do not metastasize. The detrimental nature and quick progression (median survival of about 15 months) of glioblastomas, make it almost impossible to cure these patients despite aggressive multimodal treatment strategies. Moreover, the heterogeneous nature of glioblastomas makes it extremely challenging to develop an effective therapeutic approach with a uniform outcome for all patients. Although GBMs occur almost exclusively in the brain, they can also appear in the brain stem, cerebellum, and spinal cord. In the USA, the median age of GBM diagnosis is 64 years which implies that the disease is primarily diagnosed at an older age and is usually uncommon in children.

It has also been noted that the incidence rate of glioblastoma tumors is 1.58 times higher in the male population compared to females in the US [6]. Additionally, the incidence rate of GBM is 2.5 times higher in European Americans than in African Americans and it is found to be more common in non-Hispanics than in Hispanics.

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Symptoms

Common features of GBM include increased intracranial pressure, along with headache and focal or progressive neurological deficits. The initial stage presenting symptom is a seizure in as many as 25% of patients; however, more than 50% of the patients experience this seizure at a later stage of the disease. Other common symptoms include:

  • Nausea 

  • Vomiting 

  • A decline in brain function like confusion 

  • Memory loss

  • Difficulty with balance

  • Urinary incontinence

  • Vision problems like blurred vision, double vision, or loss of peripheral vision

  • Speech difficulties

Diagnosis

The diagnosis of glioblastomas primarily depends on imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT or CAT scan) followed by biopsy with histopathological confirmation. If a biopsy cannot be performed, then the treatment is planned based only on the results of the brain scans. Immunohistochemical markers, like isocitrate dehydrogenase (IDH) mutations, (O6-Methylguanine-DNA methyltransferase) MGMT promoter methylation, (epidermal growth factor receptor) EGFR amplification/mutations, and vascular endothelial growth factor (VEGF) overexpression, are commonly assessed to ascertain the diagnosis of glioblastoma, including glial fibrillary acidic protein expression to confirm astrocytic lineage differentiation and MIB-1/Ki-67 to aid quantification of proliferation. These markers are identified by immunohistochemistry, FISH, or PCR-based methods.

Management

The mainstay of glioblastoma management is surgery, followed by radiotherapy and chemotherapy. Surgery is performed to reduce the solid tumor tissue within the brain, remove those cells in the center of the tumor that may be resistant to radiotherapy and/or chemotherapy, and reduce intracranial pressure, which may aid to prolong the lives of some patients and improve the quality of life. After the surgical wound has healed considerably, radiotherapy and chemotherapy go hand in hand. Radiotherapy is repeated for a total of 10 to 30 cycles depending on the type of tumor.

Currently, three chemotherapeutic agents named temozolamide (TMZ), bevacizumab, and carmustine have been approved by the FDA to treat patients with glioblastoma. The standard of treatment is chemotherapy with the drug temozolomide, which is administered every day during radiotherapy and then for six cycles after radiation during the maintenance phase. Tumor treating fields are another relatively new treatment modality that is introduced during the maintenance phase of radiation therapy. It creates alternating electrical fields, which prevents the growth and division of cancer cells. Lomustine (chemotherapy) and bevacizumab (targeted therapy) are usually applied when the tumor further progresses. The emergent immunotherapy can be of potential use in the future and can help to improve the prognosis of GBM.

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