GlioblastomaEdit

Glioblastoma is the most aggressive form of primary brain tumor in adults, and it sits at the severe end of the spectrum of gliomas. It originates from glial cells and is characterized by rapid growth, diffuse infiltration of surrounding brain tissue, necrosis, and abnormal blood vessel formation. Because of its infiltrative nature, complete surgical removal is rarely possible, and even after aggressive treatment the tumor almost invariably recurs. In modern classifications, glioblastoma is a WHO grade IV glioma, with molecular features used to refine prognosis and treatment decisions. The most common molecular profile in adults is IDH-wildtype, which carries a different biology and prognosis than IDH-mutant tumors. The standard treatment pathway combines maximal safe surgical resection with radiotherapy and the alkylating chemotherapy temozolomide, a regimen known for extending survival but not curing the disease. In addition to this standard approach, newer therapies such as tumor treating fields (TTFields) are being used in select settings, and a range of experimental immunotherapies and personalized approaches are under active investigation. glioma glioblastoma Temozolomide

Overview

Glioblastoma tumors arise from astrocytes or their precursors and exhibit a spectrum of histologic features, including cellular pleomorphism, regions of necrosis with pseudopalisading, microvascular proliferation, and infiltrative margins. Molecularly, GBMs show substantial heterogeneity. Common alterations include EGFR amplification, chromosome 7 gain with chromosome 10 loss, TERT promoter mutations, PTEN loss, and components of the p53 pathway, though the precise constellation varies by patient and by whether the tumor is IDH-wildtype or IDH-mutant. MGMT promoter methylation status is a clinically important biomarker that helps predict response to alkylating chemotherapy. The disease is more frequent in older adults, with a slight male predominance, and incidence varies by geography and population group. EGFR TERT promoter MGMT promoter methylation IDH1 IDH2 Tumor Treating Fields

Epidemiology

Glioblastoma affects adults across the globe, with incidence measured in the low per-100,000 range per year in many populations. The median age at diagnosis is in the sixth decade, and the disease shows a male predominance. There is regional variation in incidence and outcome, reflecting differences in diagnostic practices, access to care, and population genetics. In general, white and other populations of European ancestry have higher reported incidence in some datasets, but rates can differ substantially by region and method of ascertainment. Understanding these patterns helps researchers and clinicians anticipate outcomes and allocate resources for diagnosis and treatment. brain tumor epidemiology IDH1 IDH2

Pathology and molecular biology

Glioblastomas are defined by their histology and molecular profile. Classic histologic hallmarks include necrosis with pseudopalisading tumor cells and microvascular proliferation, but tumor cells also diffusely infiltrate beyond visible borders. Molecularly, GBMs are diverse. IDH-wildtype tumors predominate in older adults and tend to have a more aggressive clinical course, whereas IDH-mutant GBMs generally have a better prognosis and distinct biology. Common molecular alterations include EGFR amplification, PTEN loss, PDGFRA amplification, and TERT promoter mutations. MGMT promoter methylation status provides predictive information about responsiveness to temozolomide. These molecular features have shaped contemporary diagnostic criteria and therapeutic strategies. IDH1 IDH2 EGFR MGMT promoter methylation TERT promoter PTEN

Clinical presentation

Symptoms reflect the location and growth pattern of the tumor. Patients frequently present with new or worsening headaches, seizures, cognitive or personality changes, and focal neurological deficits such as weakness or language difficulties depending on the tumor's location. Rapid clinical deterioration is common due to tumor growth and edema. Because symptoms are nonspecific, imaging and tissue diagnosis are essential for distinguishing glioblastoma from other brain lesions. MRI biopsy neurosurgery

Diagnosis

Diagnostic workup begins with imaging, most often magnetic resonance imaging (MRI) with contrast, which typically shows a ring-enhancing lesion with surrounding edema and mass effect. MRI techniques such as perfusion imaging and diffusion-weighted imaging help characterize the lesion and guide biopsy. Definitive diagnosis depends on histopathology from a biopsy or resection, with molecular testing to determine IDH status, MGMT promoter methylation, and other relevant alterations that influence prognosis and treatment planning. A multidisciplinary approach integrates radiology, pathology, neurosurgery, and oncology. magnetic resonance imaging biopsy pathology IDH1 MGMT promoter methylation

Treatment

Treatment for glioblastoma is multimodal and focuses on extending survival while balancing quality of life.

Surgical management: The initial goal is maximal safe resection to reduce tumor burden and relieve mass effect, while preserving neurological function. Advances in intraoperative imaging and mapping help surgeons achieve better resections in appropriate patients. neurosurgery
Radiotherapy: Standard external beam radiotherapy is typically given in fractionated courses, commonly around 60 Gy in 30 fractions, over several weeks. Radiation aims to control residual disease after surgery and delay progression. radiotherapy
Chemotherapy: Temozolomide is given concurrently with radiotherapy and then as adjuvant therapy. The combination improved survival in landmark trials and remains a cornerstone of care. The likelihood of benefit is influenced by MGMT promoter methylation status and other tumor features. temozolomide
Tumor Treating Fields: TTFields involve delivering low-intensity alternating electric fields to the tumor region and have shown a survival benefit when added to standard therapy in some patients. The modality raises considerations about cost, practicality, and access, and debates continue about how broadly it should be used. Tumor Treating Fields
Recurrent disease and experimental approaches: At recurrence, options include repeat surgery, re-irradiation in selected cases, systemic therapies, anti-angiogenic agents in some circumstances, and participation in clinical trials. Immunotherapies, vaccines, oncolytic therapies, and personalized approaches are under investigation, with varying degrees of demonstrated benefit to date. clinical trials immunotherapy oncology

Prognosis

Prognosis in glioblastoma remains guarded. Median overall survival after diagnosis with current standard therapy is typically around 12–18 months, though outcomes vary widely based on age, performance status, tumor location, MGMT methylation, IDH status, and extent of resection. Two-year and five-year survival rates are low compared with many other cancers, reflecting the tumor’s aggressiveness and infiltrative behavior. Younger patients with good functional status and unmethylated MGMT or other favorable molecular features may experience longer survival, but long-term cure remains uncommon. prognosis MGMT promoter methylation IDH1 neurosurgery

Controversies and debates

In the field of glioblastoma, as in many areas of oncology, debates revolve around balancing efficacy, quality of life, and cost. Points of discussion include: - The value and real-world impact of TTFields, given mixed cost-benefit considerations and variability in patient experiences. Proponents point to survival gains in well-selected patients, while critics highlight logistical burdens and expense. Tumor Treating Fields - The interpretation and clinical utility of MGMT promoter methylation testing for guiding chemotherapy decisions, including insurance coverage and access to testing. MGMT promoter methylation - The role of immunotherapies and other novel agents, which have produced mixed results in GBM compared with other cancers, leading to cautious optimism tempered by concerns about safety, efficacy signals, and trial design. immunotherapy clinical trials - Classification updates reflecting molecular taxonomy (e.g., IDH status, 1p/19q codeletion) and how these influence prognosis, trial inclusion, and eligibility for targeted therapies. IDH1 IDH2 1p/19q codeletion - Access to cutting-edge therapies and the economics of care, including equitable access to imaging, biopsy, surgical expertise, radiotherapy, and maintenance treatments in diverse health system contexts. health care health economics