Glioblastoma (GBM): Causes, Symptoms, Survival Rates, and Treatment

What is Glioblastoma (GBM)?

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and most aggressive brain tumor arising from glial cells (the supporting cells of the nervous system, which provide structural support, nutrition, and insulation to neurons).

It is also the most common primary malignant brain tumor in adults overall, accounting for approximately 40% of all primary malignant central nervous system tumors. The term primary indicates that the tumor originates directly within the brain itself. This is different from metastatic tumors, which develop elsewhere in the body and later spread to the brain through metastasis.

The World Health Organization (WHO) classifies glioblastoma as a Grade IV astrocytoma, which is the highest and most aggressive grade on the brain tumor malignancy scale.

The prognosis of glioblastoma is, unfortunately, extremely poor. It is currently considered an incurable disease, with a median overall survival of approximately 14–16 months from diagnosis with optimal treatment. Only approximately 5–5.5% of patients survive five years after diagnosis, making it one of the most lethal of all human cancers.

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Causes

Despite extensive research investigating numerous potential risk factors, no clearly dominant causative factor has been identified for the vast majority of GBM cases. Like many other cancers, glioblastoma is largely sporadic and unpredictable, arising without a clearly identifiable preceding cause in most patients.

Known Risk Factors

The only well-established environmental risk factor is prior exposure to ionizing radiation, such as in these cases:

• Therapeutic cranial irradiation for previous brain tumors or leukemia
• Historical use of radiation for benign conditions (now largely discontinued)
• The latency period between radiation exposure and GBM development can be up to 20 years

Possible Protective Factors

Curiously, epidemiological studies have consistently identified several factors associated with lower GBM risk:

• History of allergies and atopic conditions (asthma, eczema, hay fever): The biological mechanism is debated, but an enhanced immune surveillance hypothesis has been proposed
• Short-term use of anti-inflammatory medications (NSAIDs): Some studies suggest a modest protective association, though causality is unproven

Factors NOT Associated with GBM

Importantly, current evidence does not support the following as significant risk factors:

• Lifestyle factors: Smoking, alcohol consumption, recreational drug use, and dietary patterns have not been convincingly linked to GBM development
• Mobile phone use: Despite significant public concern, no study to date has demonstrated a causal link between cell phone electromagnetic radiation and glioblastoma. However, researchers acknowledge that long-term (>30 years) data are still limited, and continued monitoring is warranted.

Genetics

While numerous somatic genetic mutations have been identified within GBM tumors (including alterations in EGFR, PTEN, IDH, TERT, CDKN2A, and many others), glioblastoma demonstrates virtually no hereditary familial pattern in clinical practice. The overwhelming majority of cases arise de novo (spontaneously) without any family history of brain tumors.

Key molecular markers with prognostic and therapeutic significance include:

• IDH mutation status: IDH-mutant glioblastomas (more common in younger patients and secondary GBMs) carry a significantly better prognosis than IDH-wildtype tumors
• MGMT promoter methylation: Methylation of the MGMT gene promoter predicts better response to temozolomide chemotherapy and is associated with improved survival
• EGFR amplification: Common in primary GBMs; associated with more aggressive behavior

Epidemiology and Spread

• Incidence: Approximately 2–3 new cases per 100,000 people per year in Western countries
• Age at diagnosis: GBM can occur at any age but primarily affects adults. The peak incidence falls between ages 75 and 84. Some sources, however, report the peak between 55 and 74 years, as there is minor variation between datasets.
• Sex: Approximately 1.5 times more common in men than women.
• Location: Most commonly arises in the cerebral hemispheres (particularly the temporal, frontal, and parietal lobes); less commonly in the brainstem or spinal cord.
• Metastasis outside the CNS: Extremely rare, since, like all primary brain tumors, GBM almost always remains confined within the central nervous system.

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Symptoms

The symptoms of glioblastoma are largely determined by the location and size of the tumor within the brain and are broadly similar to those produced by other brain-occupying lesions (benign or malignant). The symptoms primarily reflect two key factors: the mass effect of the tumor, or the mechanical pressure it exerts on surrounding brain structures, and focal neurological dysfunction in the area of the brain where the tumor resides.

GBM typically presents with rapidly progressive neurological symptoms that evolve over days to weeks. This notably rapid time course often prompts urgent investigation.

Most Common Presenting Symptoms

• Headache: The most frequent initial symptom. GBM headache is classically worse in the morning (due to overnight accumulation of intracranial pressure), and may awaken the patient from sleep. It often does not respond fully to standard analgesics.

• Seizures (epileptic episodes): A common presenting symptom, occurring in approximately 30 to 50% of patients at or before diagnosis. May be focal (confined to one body region) or generalized.

• Focal neurological deficits: Dysfunction specifically reflecting the area of brain affected:

  • Hemiparesis (weakness on one side of the body).
  • Hemisensory loss (reduced sensation on one side).
  • Visual field defects.
  • Aphasia, or language difficulties, occurs if the dominant hemisphere’s language areas are affected.

• Symptoms of raised intracranial pressure:

  • Nausea and vomiting, especially projectile vomiting that occurs without preceding nausea.
  • Blurred vision or double vision (diplopia)
  • Papilledema (optic disc swelling visible on eye examination)

• Cognitive and behavioral changes:

  • Memory impairment
  • Altered mental status
  • Personality changes (disinhibition, apathy, mood swings)
  • Difficulty with concentration and executive function
  • Speech difficulties

Red flags warranting urgent neurological evaluation: New-onset seizures in adulthood, progressive headache of new character, rapidly developing neurological deficits, or unexplained personality/cognitive changes should always prompt urgent clinical assessment and brain imaging.

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Survival Rates

Age, general health status, extent of surgical resection, and tumor molecular profile all influence prognosis. However, the fundamental reality remains that glioblastoma carries an extremely poor prognosis, representing one of the most lethal of all human cancers.

5-Year Relative Survival Rates by Age Group

Additional Prognostic Context

• Median overall survival with standard Stupp protocol treatment (surgery + concurrent temozolomide + radiotherapy, followed by adjuvant temozolomide): approximately 14–16 months.
• MGMT methylated GBM: Median survival improves to approximately 21–26 months with temozolomide treatment.
• IDH-mutant GBM (more common in younger patients): This subtype has a significantly better prognosis. With optimal treatment, median survival can extend to several years.
• Patients with favorable profiles (age < 50, excellent performance status, gross total resection, MGMT methylation, IDH mutation) represent the small minority who may achieve longer survival

Complications Affecting Survival and Quality of Life

Beyond disease progression itself, patients face potential complications from:

• Chemotherapy toxicity: Myelosuppression (bone marrow suppression), nausea, fatigue, opportunistic infections
• Radiotherapy effects: Radiation necrosis, cognitive changes (“radiation fog”), fatigue
• Tumor recurrence: Virtually universal, as essentially all GBMs recur after initial treatment. Second-line treatment options for recurrent GBM remain limited in efficacy.
• Thromboembolic events: GBM patients have a markedly elevated risk of deep vein thrombosis and pulmonary embolism

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Diagnosis

Clinical suspicion for a brain tumor typically arises during neurological examination, where specific focal deficits may help localize the probable area of involvement. Urgent neuroimaging is then mandatory.

Imaging Studies

MRI with gadolinium contrast enhancement is the gold standard for glioblastoma diagnosis and staging.

Classic MRI features of GBM:

• Heterogeneous central necrosis surrounded by an irregular, thick, enhancing rim
• Significant surrounding edema (bright FLAIR signal)
• Infiltration into adjacent white matter tracts
• Mass effect with midline shift
• Average tumor diameter at diagnosis: 5–10 cm

Additional advanced MRI techniques increasingly used include:

• MR Perfusion (DSC/DCE): Assesses tumor blood flow and vascularity
• MR Spectroscopy: Evaluates metabolite ratios (choline/NAA) within tumor tissue
• Diffusion-weighted imaging (DWI): Helps distinguish tumor from other lesions
• Functional MRI (fMRI): Maps eloquent cortex (language, motor areas) near the tumor for surgical planning
• DTI (Diffusion Tensor Imaging): Maps white matter tracts for surgical guidance

CT scan: Useful for rapid initial assessment (particularly in emergency settings), detection of hemorrhage, and calcifications, though less informative than MRI for tissue characterization.

Tissue Diagnosis (Biopsy)

When anatomically feasible, surgical biopsy or resection is performed to obtain tissue for:

• Histopathological confirmation of the diagnosis
• Molecular profiling: IDH mutation, MGMT methylation, EGFR amplification, TERT promoter mutation, and other markers that guide prognosis and treatment selection
• WHO grade confirmation (Grade IV)

In cases where the tumor is in a surgically inaccessible or eloquent location (near critical speech or motor areas), stereotactic needle biopsy under CT or MRI guidance provides tissue with minimal surgical risk.

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Treatment

The management of glioblastoma requires a multidisciplinary team including neurosurgeons, neuro-oncologists, radiation oncologists, neurologists, and supportive care specialists. Treatment is based on a combination of:

1. Surgery (maximum safe resection)
2. Radiotherapy (focal, stereotactic)
3. Chemotherapy (primarily temozolomide)

And in selected cases: 4. Tumor treating fields (TTFields) 5. Targeted therapies / Immunotherapy (investigational)

Surgery: Maximum Safe Resection

The goal of surgery is to achieve maximum cytoreduction (removing as much tumor as possible, ideally through gross total resection) while preserving neurological function.

Why surgery is performed:

• Reduces tumor burden and mass effect, improving neurological symptoms rapidly.
• Provides tissue for definitive histopathological and molecular diagnosis.
• Creates conditions for more effective subsequent radiotherapy and chemotherapy.
• Extent of resection is an independent predictor of survival. Specifically, gross total resection leads to significantly better outcomes than subtotal resection or biopsy alone.

Challenges: GBM’s infiltrative growth pattern means microscopic tumor cells spread well beyond the radiologically visible mass. Because of this, truly complete resection is biologically impossible.

• Proximity to eloquent brain regions (motor cortex, language areas, visual cortex) limits the extent of safe resection.

Intraoperative technologies to maximize safe resection:

• 5-ALA (5-aminolevulinic acid) fluorescence-guided surgery: Tumor cells absorb 5-ALA and emit a bright pink fluorescence under ultraviolet light. This allows surgeons to visualize and remove tumor tissue in real time, which has been proven to increase gross total resection rates.
• Intraoperative MRI: Real-time imaging during surgery to assess residual tumor
• Awake craniotomy with cortical mapping: In tumors adjacent to eloquent areas, the patient remains awake to guide safe resection while monitoring language and motor function
• Neuronavigation systems: GPS-like guidance systems integrated with pre-operative imaging

Radiotherapy

Following surgery, focal radiotherapy to the tumor bed and surrounding margins is a cornerstone of GBM treatment.

Standard protocol:

• 60 Gy delivered in 30 fractions (6 weeks) to a defined target volume around the surgical resection cavity
• Concurrent with temozolomide chemotherapy (Stupp protocol)
• For elderly patients (> 65–70 years) or those with poor performance status: hypofractionated regimens (e.g., 40 Gy in 15 fractions) achieve similar outcomes with reduced treatment burden

Chemotherapy: Temozolomide (TMZ)

Temozolomide (brand name Temodar® / Temodal®) is the standard chemotherapeutic agent for GBM:

• Concurrent phase: Taken daily (75 mg/m²/day) throughout the 6-week radiotherapy course
• Adjuvant phase: 6 cycles of 5-days-on/23-days-off dosing (150–200 mg/m²/day) following radiotherapy completion

MGMT methylation status is critical:

• In MGMT-methylated tumors: Temozolomide provides substantial benefit (median survival ~21–26 months)
• In MGMT-unmethylated tumors: Benefit is more modest; alternative strategies are under investigation

Tumor Treating Fields (TTFields / Optune®)

Optune® is a wearable, non-invasive device delivering low-intensity alternating electric fields to the scalp through adhesive transducer arrays. These electric fields interfere with the mitotic spindle during cell division, selectively disrupting the replication of rapidly dividing GBM cells.

• EF-14 trial results: Addition of TTFields to standard temozolomide maintenance improved median overall survival from 16.0 to 20.9 months in newly diagnosed GBM, with 5-year survival improving from 5% to 13%
• TTFields are now incorporated into NCCN guidelines as a standard treatment option for newly diagnosed GBM in patients with good performance status
• Limitation: Device must be worn for ≥18 hours/day, requires shaved scalp, and involves adherence challenges

Bevacizumab (Avastin®)

An anti-VEGF monoclonal antibody (anti-angiogenic therapy) that reduces tumor vascularization. Approved for recurrent GBM; while it improves progression-free survival and reduces cerebral edema (allowing corticosteroid dose reduction), it has not demonstrated improved overall survival in clinical trials for newly diagnosed GBM.

Immunotherapy and Targeted Therapy (Investigational)

Multiple investigational approaches are under active clinical trial investigation:

• Immune checkpoint inhibitors (PD-1/PD-L1 inhibitors, CTLA-4 inhibitors): So far yielding disappointing results in unselected GBM populations; subgroup analyses ongoing
• CAR-T cell therapy: Early-phase trials targeting GBM-specific antigens (EGFRvIII, IL13Rα2, GD2)
• EGFR-targeted therapies: Limited success to date due to tumor heterogeneity
• IDH inhibitors: Showing promise in IDH-mutant gliomas (Grade 2–3); role in IDH-mutant GBM under investigation
• Vaccine-based approaches: Personalized peptide vaccines and dendritic cell vaccines under investigation
• Oncolytic viral therapy: Directly infecting and destroying tumor cells with modified viruses

Pseudoprogression

An important and frequently encountered imaging pitfall in GBM management is pseudoprogression.

Definition: An apparent worsening of MRI findings, such as increased enhancement, edema, or lesion size, may occur in the first 3 months following completion of concurrent chemoradiotherapy. This change does not represent true disease progression.

Mechanism: Pseudoprogression is a treatment-related inflammatory and necrotic response to radiotherapy and temozolomide, not actual tumor growth.

Clinical significance: Distinguishing pseudoprogression from true tumor recurrence is critically important: Misidentifying pseudoprogression as recurrence may result in the premature discontinuation of effective treatment, which could have catastrophic consequences.

• The key distinguishing feature: In pseudoprogression, the patient typically shows no clinical deterioration. Despite worsening imaging, neurological status remains stable or may even improve.

Advanced imaging tools to help distinguish:

• MR Perfusion: Reduced cerebral blood volume in pseudoprogression vs. elevated in true recurrence
• MR Spectroscopy: Decreased choline in pseudoprogression vs. elevated in true tumor
• 18F-FDG or 18F-FDOPA PET-CT: Metabolic imaging to differentiate active tumor from necrosis

When in doubt, close clinical monitoring with repeat imaging at 4–6 week intervals is preferred over immediate treatment change.

Supportive Therapy

An essential and often underemphasized dimension of GBM management is supportive (palliative) care. This involves a comprehensive, multidisciplinary approach that includes:

• Relieving symptoms
• Maintaining neurological function
• Preserving quality of life
• Supporting patients and families throughout the illness trajectory

Key components include:

Antiepileptic Drugs (AEDs)

• Indicated for patients who have experienced seizures. Prophylactic AEDs, however, are not recommended routinely in patients who have not had seizures.
• Preferred agents: Levetiracetam (Keppra®), which is preferred due to its minimal drug-drug interactions with chemotherapeutic agents and favorable tolerability profile. Alternatives include valproic acid, lacosamide, and others.

Corticosteroids

• Dexamethasone is the most commonly used agent.
• Mechanism: Reduces vasogenic cerebral edema and tumor mass effect.
• Often provides rapid, dramatic symptomatic relief from headache, frequently within 24–48 hours of initiation.
• Important considerations: Use at the lowest effective dose for the shortest possible duration due to significant side effects with prolonged use (hyperglycemia, immunosuppression, muscle wasting, osteoporosis, psychiatric effects).

Thromboprophylaxis

• GBM patients have a very high risk of venous thromboembolism (DVT, pulmonary embolism)
• Low molecular weight heparin (LMWH) is indicated for treatment; prophylaxis in high-risk situations

Palliative and Psychological Care

• Early integration of palliative care, starting from the time of diagnosis rather than just in the terminal phase, is associated with improved quality of life and symptom control.
• Psychological support for patients and families: Coping with a glioblastoma diagnosis profoundly impacts mental health; access to clinical psychology, social work, and peer support groups is essential
• Rehabilitation: Physiotherapy, occupational therapy, and speech therapy to address and partially restore neurological deficits

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Sources and Bibliography

• Kanderi T, Gupta V. Glioblastoma Multiforme. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK558954/

• American Cancer Society. Survival Rates for Selected Adult Brain and Spinal Cord Tumors. https://www.cancer.org/cancer/types/brain-spinal-cord-tumors-adults/detection-diagnosis-staging/survival-rates.html

• Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine. 2005;352(10):987-996. https://doi.org/10.1056/NEJMoa043330

• Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial (EF-14). JAMA. 2017;318(23):2306-2316. https://doi.org/10.1001/jama.2017.18718

• Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncology. 2021;23(8):1231-1251. https://doi.org/10.1093/neuonc/noab106

• Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nature Reviews Clinical Oncology. 2021;18(3):170-186. https://doi.org/10.1038/s41571-020-00447-z

• Hegi ME, Diserens AC, Gorlia T, et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. New England Journal of Medicine. 2005;352(10):997-1003. https://doi.org/10.1056/NEJMoa043331

• Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncology. 2006;7(5):392-401. https://doi.org/10.1016/S1470-2045(06)70665-9

• National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 2.2023. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425