Glioblastoma
Epidemiology and survival
Incidence
Glioblastoma (GBM) is known to be the most aggressive and most common primary malignant tumor of the brain and central nervous system, accounting for more than 60% of brain tumors in adults.1-4 These tumors originate from astrocytic glial cells and are categorized as high-grade malignant gliomas (grade IV) due to their aggressive, invasive, and undifferentiated characteristics.1,3
GBM is known to be a rare tumor with a global incidence of <10 per 100,000 population, with the highest incidence noted in North America, Australia, as well as Northern and Western Europe.1-4 In the United States, the most recent average age-adjusted incidence rate is 4.23 per 100,000 population with an overall prevalence of 9.3 per 100,000 population.4 GBM is about 1.6 times more common in males compared to females, and can occur at any age with majority of cases diagnosed in people over 40 years old.1,3-4
Compared to other malignancies, risk factors for GBM are quite limited with the strongest risk attributed to previous exposure to ionizing radiation.1,4 Other factors such as previous treatment due to acute lymphoid leukemia, presence or absence of atopy/allergies, ovarian steroid hormones, and co-existing genetic disorders such as tuberous sclerosis contribute as well to the risk of GBM, but with minimal influence.1
Survival
Patients diagnosed with GBM have a generally poor prognosis, with a low median overall survival of 10 to 15 months post-diagnosis.1-3 Despite therapeutic advances and improved short-term survival rates, the five-year survival rate also remains low at 5.1-5.8%.2,4
Advanced age, poor performance status, and incomplete extent of resection from surgery are negative prognostic factors that contribute to the low survival rate of GBM, while the presence of certain molecular features such as isocitrate dehydrogenase 1 (IDH-1) and 2 (IDH-2) mutations as well as MGMT methylation are positive prognostic factors.4
With the advent of new research, commonly identified genetic alterations for GBM have been identified and have served as prognostic indices for patients. Drugs targeting many of these identified alterations are currently being investigated as potential therapies for the disease.2
Common genetic alterations in GBM2
Adapted from Taylor O, et al. Front Oncol. 2019 Sept 26;9:963.2
Classification
Glioblastomas fall under the same category of gliomas, and follow the international standard for nomenclature and diagnosis according to the 2016 World Health Organization (WHO):3
Glioblastoma IDH wildtype – found in 90% of glioblastoma cases, developing de novo at about 60 years of age
Glioblastoma IDH-mutant – found in about 10% of glioblastoma cases, carrying a significantly better prognosis compared to those with the IDH wildtype; usually develop as a secondary GBM in younger patients with gliomas of high differentiation (WHO grades I-III)
Glioblastoma not otherwise specified (NOS) – IDH mutation cannot be determined due to a lack of histological or molecular testing
Not-elsewhere-classified (NEC) glioblastoma – after evaluation, the tumor does not match to any of the aforementioned categories; there are possible discrepancies between the clinical, histological, immunological, and genetic features of the tumor
Presentation and diagnosis
For the diagnosis of GBM, invasive catheter angiography or non-invasive computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used. Out of all of these imaging modalities, the gold standard recommended for diagnosis is the cranial MRI since the soft tissue enhancement helps visualize the complexity and heterogeneity of the tumor.1 GBM is most frequently located in the supratentorial region in 95% of cases, commonly in the cerebral hemispheres (frontal lobe); the other 5% of tumors occur in different areas of the central nervous system such as the cerebellum, brainstem, and spinal cord.1,3
Symptoms of GBM can develop gradually over the course of a number of years, or rapidly similar to a stroke. Direct effects of the tumor may cause focal neural deficit and cognitive impairments due to brain tissue necrosis, corresponding to the specific region it is located in. Secondary tumor effects due to increased intracranial pressure such as headaches, vomiting, or papilledema are hallmarks in GBM with 30-50% of patients experiencing these symptoms. About 20-40% of patients have also experienced seizures, usually with a focal onset that may present as simple partial, complex partial, or generalized.1
Clinical management
The primary treatment for GBM is surgical resection of the tumor (if applicable) followed by radiotherapy and concomitant chemotherapy. The process of maximal surgical resection offers the opportunity for accurate histological diagnosis, tumor genotyping, and reduction in tumor volume.1-4 However, due to the aggressive and invasive nature of the tumor, surgery does not offer curative results and relapse occurs frequently in 80% of cases within 2-3cm of the margin of the original lesion. Majority of patients that have undergone surgery proceed to stereotactic radiotherapy to further improve survival outcomes, but for some subgroups of patients this may be unfavorable.1,2,4
As an adjuvant to surgery and radiotherapy, chemotherapy with alkylating agents such as temozolomide greatly improves outcomes and the combination of the three modalities is becoming the standard of care for patients with GBM.1-4 However, due to increased risk of treatment resistance, once patients have exhausted these options and recurrence occurs, treatment options become extremely limited.2
A number of new drugs are being investigated to expand the treatment options and outcomes of GBM patients. Inhibition of the interaction between MDM2 and p53 has emerged as a potential strategy and MDM2 inhibitors are undergoing clinical trials to evaluate their efficacy and safety for GBM therapy.5
In addition to novel targeted therapies, a multimodality therapeutic approach can potentially improve patient outcomes and quality of life, especially for those in the recurrent or relapsed setting.4
Hanif F, et al. Asian Pac J Cancer Rev 2017;18(1):3-9.
Taylor O, et al. Front Oncol 2019;9:963.
Grochans S, et al. Cancers 2022;14:2412.
Tan A, et al. CA Cancer J Clin 2020;70:299-312.
Pellot Ortiz K, et al. Biomedicines 2023;11(7):1879.