Glioblastoma (GBM)

1. Clinical Overview

Summary

Glioblastoma is the most common and most aggressive primary malignant brain tumour in adults, representing approximately 45-50% of all malignant primary brain tumours. [1] It is classified as a WHO Grade 4 astrocytoma characterized by rapid, diffusely infiltrative growth, microvascular proliferation, and necrosis. Despite maximal multimodal therapy, the median overall survival remains approximately 14-15 months, with a 5-year survival rate of less than 5%. [2,3]

The 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5) fundamentally redefined glioblastoma, requiring IDH-wildtype status for the diagnosis. [4] Tumors previously classified as "secondary glioblastoma" (IDH-mutant grade 4 astrocytomas arising from lower-grade precursors) are now designated as "Astrocytoma, IDH-mutant, Grade 4" and carry a significantly better prognosis. This molecular reclassification represents a paradigm shift from purely histological to integrated histo-molecular diagnostics.

The disease predominantly affects older adults with a median age at diagnosis of 64 years, though it can occur across all age groups. [5] Men are affected more commonly than women with a male-to-female ratio of approximately 1.6:1. Survival is influenced by multiple factors including age, performance status, extent of resection, and molecular biomarkers, particularly MGMT promoter methylation status.

Key Facts

Butterfly Glioma: A hallmark radiological pattern where the tumour crosses the midline via the corpus callosum, resembling butterfly wings on axial imaging. This bilateral involvement portends a particularly poor prognosis as complete surgical resection is impossible.

MGMT Promoter Methylation: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine, thereby counteracting the cytotoxic effects of alkylating chemotherapy agents like temozolomide. When the MGMT promoter is methylated (epigenetically silenced), the enzyme is not produced, rendering tumor cells unable to repair temozolomide-induced DNA damage. MGMT methylation is found in approximately 40-45% of glioblastomas and is associated with significantly improved response to temozolomide and prolonged survival (median OS 21.7 months vs 12.7 months in unmethylated tumors). [6,7]

5-Aminolevulinic Acid (5-ALA) Fluorescence: Patients receive oral 5-ALA (20 mg/kg body weight) 3-4 hours before surgery. Under blue-violet light (wavelength 375-440 nm), metabolized protoporphyrin IX accumulates preferentially in glioblastoma cells, causing them to fluoresce bright pink. This fluorescence-guided surgery has been shown to increase the rate of complete resection and improve progression-free survival. [8]

Clinical Pearls

The Dexamethasone Effect: The clinical syndrome caused by a glioblastoma often reflects 20% tumor mass and 80% vasogenic edema. High-dose dexamethasone (8-16 mg daily in divided doses) can produce dramatic neurological improvement within 24-48 hours by reducing capillary permeability and edema. This can transform a comatose patient into one who is alert and conversant. However, this is purely symptomatic relief—the tumor remains unchanged. Prolonged corticosteroid use carries significant morbidity including hyperglycemia, myopathy, psychiatric effects, and increased infection risk.

Morning Headache and ICP Physiology: The classic "brain tumor headache" (worse on waking, improves when upright) reflects nocturnal CO2 retention during sleep (causing cerebral vasodilation) and the supine position increasing intracranial pressure. The headache may be accompanied by nausea/vomiting and improve after vomiting (transient ICP reduction).

First Seizure in Adults: A first unprovoked seizure in an adult over 25 years mandates neuroimaging (MRI preferred over CT) to exclude structural pathology, particularly brain tumors. Approximately 30-50% of glioblastoma patients present with seizures. [9]

Pseudoprogression vs True Progression: Following chemoradiotherapy, approximately 20-30% of patients develop increased contrast enhancement and edema on MRI within 3 months of completing radiotherapy. This "pseudoprogression" represents treatment-related inflammation rather than tumor growth and typically stabilizes or resolves without treatment modification. Distinguishing pseudoprogression from true tumor progression is challenging; advanced imaging (perfusion MRI, PET) and clinical stability favor pseudoprogression.

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2. Epidemiology

Incidence and Prevalence

• Global Incidence: 3-4 per 100,000 population per year in Europe and North America. [10]
• Age-Specific Incidence: Rare before age 40; incidence increases steadily with age, peaking in the 7th-8th decades.
• Median Age at Diagnosis: 64 years. [5]
• Sex Distribution: Male predominance with M:F ratio of 1.6:1. [5]

Geographic and Ethnic Variation

Incidence is highest in developed countries, particularly among non-Hispanic white populations. Lower rates are observed in Asian and African populations, though this may partly reflect differences in diagnostic access and tumor registry reporting.

Risk Factors

Established Risk Factors:

• Ionizing Radiation: The only consistently proven environmental risk factor. Therapeutic cranial irradiation (e.g., for childhood leukemia) increases glioblastoma risk with a latency period of 10-30 years. Even low-dose dental x-rays have been associated with increased risk in some studies. [11]

Unproven/Controversial Risk Factors:

• Mobile Phones: Despite extensive research, no consistent evidence links mobile phone use to glioblastoma risk. Major epidemiological studies (INTERPHONE, Million Women Study) have not demonstrated increased incidence. [12]
• Occupational Exposures: Weak associations reported for vinyl chloride, petrochemicals, and rubber manufacturing, but evidence remains inconsistent.

Genetic Predisposition:

• Hereditary Syndromes (rare, account for less than 5% of cases):
  • Neurofibromatosis Type 1 (NF1)
  • Li-Fraumeni syndrome (TP53 germline mutations)
  • Lynch syndrome (mismatch repair gene mutations)
  • Turcot syndrome (APC or mismatch repair gene mutations)

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3. Pathophysiology

Molecular Classification (WHO 2021)

The 2021 WHO Classification fundamentally redefined glioblastoma based on molecular characteristics: [4]

1. Glioblastoma, IDH-wildtype (WHO Grade 4)

• The "classic" glioblastoma
• Accounts for approximately 90% of cases
• Arises de novo (primary glioblastoma) without precursor lesion
• Typically affects older patients (median age 62 years)
• Worst prognosis: median OS 12-15 months
• Common molecular alterations:
  • TERT promoter mutations (70-80%)
  • EGFR amplification/mutation (40-50%)
  • PTEN loss (25-40%)
  • +7/-10 (chromosome 7 gain/chromosome 10 loss, ~80%)
  • TP53 mutations (25-30%)
  • CDKN2A/B homozygous deletion (50-60%)

2. Astrocytoma, IDH-mutant, Grade 4

• Formerly called "secondary glioblastoma"
• Arises from progressive malignant transformation of lower-grade IDH-mutant astrocytomas
• Accounts for approximately 10% of grade 4 gliomas
• Typically affects younger patients (median age 44 years)
• Better prognosis: median OS 24-31 months
• Universal IDH1 or IDH2 mutation
• TP53 mutations (> 80%)
• ATRX loss (> 80%)

Histopathological Features

Diagnostic Hallmarks:

1. Pseudopalisading Necrosis: Ribbons of viable tumor cells arranged in palisades around zones of ischemic necrosis. This pattern reflects rapid tumor growth outpacing vascular supply, leading to central hypoxia and necrosis, with viable cells migrating away from necrotic zones.

2. Microvascular Proliferation: Abnormal, glomeruloid capillary tufts formed by endothelial cell proliferation. Driven by VEGF (vascular endothelial growth factor) secretion by hypoxic tumor cells, these vessels are structurally abnormal and leaky, contributing to vasogenic edema.

3. Cellular Pleomorphism: Marked variation in cell size, shape, and nuclear morphology, including bizarre multinucleated giant cells.

4. High Mitotic Activity: Numerous mitotic figures reflecting rapid cell division.

5. Infiltrative Growth Pattern: Tumor cells extensively infiltrate adjacent brain parenchyma along white matter tracts, extending far beyond visible tumor margins on imaging (explaining inevitable recurrence despite "complete" resection).

Molecular Pathogenesis

Glioblastoma development involves progressive accumulation of genetic and epigenetic alterations affecting key pathways:

1. Receptor Tyrosine Kinase (RTK) Signaling Pathway

• EGFR amplification/mutation (most common alteration)
• PDGFRA amplification
• MET amplification
• Results in constitutive activation of downstream PI3K/AKT and RAS/MAPK signaling promoting proliferation and survival

2. TP53 Pathway

• TP53 mutations or MDM2/MDM4 amplification
• Loss of cell cycle checkpoint control and apoptosis

3. RB Pathway

• CDKN2A/B deletion (p16INK4a and p14ARF)
• CDK4/6 amplification
• RB1 mutations
• Loss of G1/S cell cycle checkpoint

4. PTEN/PI3K/AKT Pathway

• PTEN loss (tumor suppressor)
• PIK3CA/PIK3R1 mutations
• Promotes cell survival, growth, and metabolism

Tumor Microenvironment

Glioblastomas create an immunosuppressive microenvironment through multiple mechanisms:

• Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs): Comprise up to 30-50% of tumor mass, promoting immune evasion
• Low Mutational Burden: Despite aggressive behavior, glioblastomas have relatively few mutations compared to other cancers, limiting neoantigen generation for immune recognition
• PD-L1 Expression: Variable, contributes to T-cell exhaustion
• Blood-Brain Barrier: Limits immune cell infiltration and therapeutic agent delivery

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4. Clinical Presentation

Presenting Symptoms

Clinical presentation depends on tumor location, size, rate of growth, and degree of mass effect/edema.

Raised Intracranial Pressure (50-60% of patients)

• Headache: Progressive, worse in morning, worsened by Valsalva maneuvers (coughing, straining, bending forward)
• Nausea and Vomiting: Often projectile, worse in morning
• Visual Disturbances: Blurred vision, transient visual obscurations (papilledema), diplopia (VI nerve palsy)
• Altered Consciousness: Drowsiness, lethargy, confusion

Seizures (30-50% of patients) [9]

• Often the presenting symptom, particularly with cortical lesions
• Focal Seizures: With or without impaired awareness, may have secondary generalization
• Generalized Tonic-Clonic Seizures: May occur de novo or secondary to focal onset
• New-onset seizures in adults over 25 years mandates neuroimaging

Focal Neurological Deficits (40-50% of patients)

Location-dependent signs:

• Frontal Lobe: Personality change, executive dysfunction, disinhibition, apathy, motor weakness (precentral gyrus), expressive aphasia (dominant inferior frontal—Broca's area)
• Temporal Lobe: Memory impairment, receptive aphasia (dominant superior temporal—Wernicke's area), visual field defects (superior quadrantanopia from optic radiation involvement)
• Parietal Lobe: Sensory deficits, neglect syndrome, apraxia, acalculia, agraphia, Gerstmann syndrome
• Occipital Lobe: Visual field defects (homonymous hemianopia)
• Corpus Callosum: Alien hand syndrome, split-brain phenomena (rare, in butterfly gliomas)
• Deep Structures: Movement disorders (basal ganglia), memory deficits (thalamus)

Neuropsychiatric Symptoms

• Personality change, mood disturbance (depression, apathy)
• Cognitive decline: memory impairment, executive dysfunction
• Behavioral disinhibition, poor judgment
• Often subtle initially, may be attributed to normal aging or psychiatric illness

Rate of Symptom Progression

Glioblastoma typically presents with rapidly progressive symptoms over weeks to months, contrasting with lower-grade gliomas (which may present over years) and metastases (which can present acutely).

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5. Clinical Examination

General Examination

• Vital Signs: Cushing's triad in severe raised ICP (bradycardia, hypertension, irregular respirations—late finding)
• Mental Status: Glasgow Coma Scale, Mini-Mental State Examination, or Montreal Cognitive Assessment
• General Inspection: Cachexia, signs of chronic corticosteroid use

Neurological Examination

Fundoscopy

• Papilledema: Blurred disc margins, elevated optic disc, absent venous pulsations, hemorrhages/exudates
• Absence does not exclude raised ICP (papilledema develops over days to weeks)

Cranial Nerves

• II: Visual acuity, visual fields (confrontation testing), afferent pupillary defect
• III, IV, VI: Eye movements, diplopia, ptosis; VI nerve palsy (false localizing sign of raised ICP)
• VII: Facial asymmetry (distinguishing UMN vs LMN pattern)
• IX, X, XII: Bulbar function if brainstem involvement

Motor System

• Pattern: Hemiparesis (UMN pattern) with contralateral motor cortex involvement
• Tone: Spasticity (UMN lesion), hypotonia acutely
• Power: MRC grading 0-5
• Reflexes: Hyperreflexia, clonus
• Plantar Response: Upgoing (Babinski sign, UMN lesion)

Sensory System

• Cortical sensory loss (parietal lesions): Astereognosis, graphesthesia, two-point discrimination
• Sensory neglect/inattention

Coordination and Gait

• Cerebellar signs if posterior fossa involvement (rare for supratentorial glioblastoma)
• Gait apraxia, frontal gait disorder

Higher Cortical Functions

• Language: Fluency, comprehension, repetition, naming (Boston Diagnostic Aphasia Examination)
• Memory: Short-term and long-term recall
• Executive Function: Planning, judgment, abstract reasoning
• Visuospatial Function: Clock drawing, constructional ability

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6. Investigations

Neuroimaging

MRI Brain with Contrast (Gold Standard) [13]

Sequences:

• T1-weighted: Hypointense to isointense mass
• T1-weighted post-gadolinium: Irregular, thick ring enhancement (hallmark feature) due to blood-brain barrier disruption and neovascularization. Central non-enhancing necrosis.
• T2-weighted/FLAIR: Hyperintense mass with extensive surrounding vasogenic edema (hyperintense, finger-like projections along white matter tracts)
• DWI (Diffusion-Weighted Imaging): Variable, restricted diffusion in cellular areas, facilitated diffusion in necrotic regions
• SWI (Susceptibility-Weighted Imaging): Hemorrhage, calcification, tumor vascularity

Characteristic Imaging Features:

• Rim-enhancing mass with central necrosis
• Extensive vasogenic edema (T2/FLAIR hyperintensity) disproportionate to tumor size
• Mass effect: Midline shift, sulcal effacement, ventricular compression
• Infiltrative margins: Irregular, ill-defined borders with extension along white matter tracts
• "Butterfly" pattern: Corpus callosum involvement with bilateral hemispheric extension
• Subependymal spread: Tracking along ventricular walls

Advanced MRI Techniques:

• MR Spectroscopy: Elevated choline (membrane turnover), decreased N-acetylaspartate (NAA, neuronal loss), lactate peak (anaerobic metabolism), possible lipid peaks (necrosis)
• Perfusion MRI (DSC/DCE): Elevated relative cerebral blood volume (rCBV) reflecting neoangiogenesis; helps distinguish recurrent tumor (high perfusion) from radiation necrosis (low perfusion)
• MR Tractography (DTI): Preoperative mapping of white matter tracts (corticospinal tract, arcuate fasciculus) to plan safe surgical corridors

CT Brain (Alternative When MRI Contraindicated)

• Unenhanced: Hypodense to isodense mass, central hypodensity (necrosis), surrounding hypodense edema
• Contrast-Enhanced: Irregular rim enhancement
• Less sensitive than MRI for detecting tumor extent, infiltration, and posterior fossa lesions

PET Imaging

• FDG-PET: High metabolic activity (increased glucose uptake), but limited specificity
• Amino Acid PET (11C-methionine, 18F-FET, 18F-FDOPA): Higher specificity for tumor vs inflammation, useful for distinguishing progression from pseudoprogression or radiation necrosis. [14]

Tissue Diagnosis

Stereotactic Biopsy vs Open Resection:

• Stereotactic Biopsy: For lesions in eloquent cortex, deep structures, or patients unfit for craniotomy. Frameless or frame-based navigation. Diagnostic yield > 95%, but sampling error possible in heterogeneous tumors.
• Open Craniotomy with Resection: Preferred when safe resection feasible; provides tissue for comprehensive histopathological and molecular analysis while offering therapeutic benefit (cytoreduction).

Histopathological Analysis:

• Hematoxylin and Eosin (H&E): Identifies pseudopalisading necrosis, microvascular proliferation
• Immunohistochemistry: GFAP (glial fibrillary acidic protein) positive, confirming glial origin
• Ki-67 Proliferation Index: Typically > 20% (high proliferative activity)

Molecular Testing (Essential per WHO 2021): [4]

• IDH1/IDH2 Mutation Status: Immunohistochemistry (IDH1 R132H antibody) followed by sequencing if negative. IDH-wildtype required for glioblastoma diagnosis.
• MGMT Promoter Methylation: Methylation-specific PCR or pyrosequencing. Predicts temozolomide response. [6,7]
• TERT Promoter Mutation: C228T or C250T mutations
• EGFR Status: Amplification (FISH), EGFRvIII deletion mutation (immunohistochemistry/PCR)
• Chromosome 7 Gain/10 Loss: FISH or chromosomal microarray
• 1p/19q Codeletion: Excludes oligodendroglioma (1p/19q codeleted tumors are not glioblastoma)

Laboratory Investigations

Baseline Blood Tests:

• Full blood count (FBC): Baseline before chemotherapy
• Urea and electrolytes (U&E): Renal function
• Liver function tests (LFTs): Hepatic function before chemotherapy
• Coagulation screen: Preoperative assessment
• Glucose: Often elevated on corticosteroids

Tumor Markers:

• None clinically useful for diagnosis or monitoring

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7. Differential Diagnosis

Primary CNS Tumors

1. Brain Metastases

   • Often multiple (glioblastoma usually solitary)
   • Known primary malignancy (lung, breast, melanoma, renal, colorectal)
   • More circumscribed, less infiltrative on imaging
   • Gray-white matter junction location typical

2. Primary CNS Lymphoma

   • Immunocompromised patients (HIV, post-transplant) or elderly immunocompetent
   • Homogeneous enhancement (not ring-enhancing)
   • Periventricular location, may cross corpus callosum
   • Restricted diffusion on DWI
   • Dramatic response to corticosteroids (may temporarily disappear on imaging—"vanishing tumor")

3. Anaplastic Astrocytoma (WHO Grade 3)

   • IDH-mutant astrocytomas with anaplastic features
   • Less aggressive, better prognosis than glioblastoma
   • Non-enhancing or minimal enhancement
   • Absence of necrosis and microvascular proliferation histologically

4. Lower Grade Gliomas (WHO Grade 2)

   • Non-enhancing, infiltrative T2/FLAIR hyperintense masses
   • Younger patients, slower growth
   • IDH-mutant more common

Inflammatory/Infectious Lesions

5. Cerebral Abscess

   • Fever, systemic signs of infection
   • Thin, smooth rim enhancement (vs irregular thick rim in GBM)
   • Restricted diffusion in abscess cavity (pus)
   • Adjacent meningeal enhancement

6. Tumefactive Demyelination (MS Pseudotumor)

   • Younger patients, history of MS or first demyelinating event
   • Large (> 2 cm) demyelinating plaque mimicking tumor
   • Incomplete ring enhancement, open-ring sign
   • Peripheral restricted diffusion
   • CSF oligoclonal bands, elevated IgG index

Vascular Lesions

7. Subacute Cerebral Infarct
   • Vascular territory distribution
   • Mass effect peaks at days 3-7 post-stroke
   • Gyriform enhancement (cortical ribbon)
   • Restricted diffusion in acute phase

Other

8. Radiation Necrosis (in previously irradiated patients)

   • History of prior cranial radiotherapy
   • Enhancing mass with surrounding edema
   • Low perfusion on perfusion MRI (vs high perfusion in tumor)
   • May require biopsy to distinguish from recurrence

9. Toxoplasmosis (in HIV/AIDS patients)

   • Multiple ring-enhancing lesions
   • Basal ganglia predilection
   • Positive Toxoplasma serology
   • Response to empiric anti-toxoplasma therapy

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8. Management

The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection followed by the Stupp Protocol: concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide. [2,15]

Management Algorithm

        SUSPECTED GLIOBLASTOMA (Imaging)
                     ↓
         Dexamethasone if mass effect/edema
         Anti-epileptics if seizures
                     ↓
     ┌────────────────────────────────────┐
     │                                    │
RESECTABLE                          UNRESECTABLE
     │                                    │
MAXIMAL SAFE RESECTION            STEREOTACTIC BIOPSY
(+/- 5-ALA guidance)
(+/- Intraoperative monitoring)
     │                                    │
     └────────────────┬───────────────────┘
                      ↓
         HISTOPATHOLOGICAL DIAGNOSIS
         Molecular profiling (IDH, MGMT, etc.)
                      ↓
         MULTIDISCIPLINARY TEAM REVIEW
                      ↓
           STUPP PROTOCOL (if PS 0-2)
                      ↓
      ┌─────────────────────────────┐
      │                             │
CONCURRENT PHASE            ADJUVANT PHASE
(6 weeks)                   (6 months)
      │                             │
Radiotherapy 60 Gy          Temozolomide
(30 fractions)              (5/28 day cycles)
+                           Dose: 150-200 mg/m²
Temozolomide 75 mg/m²       days 1-5
(daily, including weekends)
      │                             │
      └──────────────┬──────────────┘
                     ↓
           SURVEILLANCE MRI
           (every 2-4 months)
                     ↓
        ┌────────────┴────────────┐
        │                         │
    STABLE                    PROGRESSION
        │                         │
    CONTINUE                  RECURRENT GBM
    SURVEILLANCE              MANAGEMENT OPTIONS

Acute/Supportive Management

Corticosteroids

• Indication: Vasogenic edema, mass effect, symptomatic relief
• Agent: Dexamethasone (minimal mineralocorticoid activity)
• Dosing:
  • "Mild symptoms: 4-8 mg daily (divided doses)"
  • "Moderate-severe: 8-16 mg daily"
  • "Critical/pre-operative: Up to 16-24 mg daily (IV if unable to take PO)"
• Tapering: Gradual taper after surgery/radiotherapy to minimize withdrawal and rebound edema
• Side Effects: Hyperglycemia, myopathy, insomnia, psychiatric effects, GI bleeding, immunosuppression (Pneumocystis jirovecii prophylaxis if prolonged high-dose)
• Gastroprotection: Proton pump inhibitor (e.g., omeprazole 20 mg daily)

Anti-Epileptic Drugs (AEDs)

• NOT Recommended Prophylactically: Meta-analyses show no benefit of prophylactic AEDs in patients without seizures. [16]
• Indications for AEDs:
  • Documented seizures
  • Cortical location with high seizure risk
• First-Line Agents: Levetiracetam (1000-3000 mg/day divided BID)—no hepatic enzyme induction, favorable side effect profile
• Alternatives: Lacosamide, lamotrigine
• Avoid: Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) due to increased temozolomide metabolism

Venous Thromboembolism (VTE) Prophylaxis

• Risk: Glioblastoma patients have high VTE risk (tissue factor secretion, immobility, hypercoagulable state)
• Prophylaxis: Low molecular weight heparin (LMWH)—balance thrombosis risk against intracranial hemorrhage
• Post-operative: LMWH initiated 24-48 hours post-operatively if no bleeding complications

Surgical Management

Goal: Maximal safe resection without causing new permanent neurological deficits. [17]

Evidence: Extent of resection (EOR) correlates with survival. Gross total resection (GTR, > 98-99% resection) associated with median OS 15-17 months vs 11-12 months for subtotal resection. [17]

Surgical Techniques

1. Image-Guided Neuronavigation: Frameless stereotaxy using pre-operative MRI for real-time intraoperative localization

2. Intraoperative MRI (iMRI): Allows assessment of resection extent during surgery, guiding further resection

3. 5-Aminolevulinic Acid (5-ALA) Fluorescence-Guided Surgery: [8]

   • Oral 5-ALA (20 mg/kg) given 3-4 hours pre-operatively
   • Blue-violet light (400-410 nm wavelength) excitation
   • Tumor cells fluoresce pink (protoporphyrin IX accumulation)
   • Improves GTR rates and 6-month PFS (41% vs 21%)

4. Awake Craniotomy with Cortical/Subcortical Mapping: For tumors in eloquent cortex (motor, language areas)

   • Intraoperative neurophysiological monitoring
   • Direct cortical stimulation mapping language (Broca's, Wernicke's areas)
   • Motor evoked potentials (MEPs), somatosensory evoked potentials (SSEPs)

5. Intraoperative Ultrasound: Real-time imaging of resection cavity

Complications:

• Neurological deficits (permanent 4-8%, transient higher)
• Intracranial hemorrhage (1-3%)
• Infection (1-3%)
• CSF leak
• Seizures

Radiotherapy

Dosing: 60 Gy in 30 fractions (2 Gy per fraction) over 6 weeks to the tumor bed plus 2-3 cm margin. [2]

Technique:

• Intensity-Modulated Radiotherapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT)
• 3D conformal planning to minimize dose to normal brain, optic apparatus, brainstem

Modifications for Elderly/Poor Performance Status:

• Hypofractionated Radiotherapy: 40 Gy in 15 fractions (non-inferior to 60 Gy in 30 fractions for patients > 65 years or poor PS)

Chemotherapy: The Stupp Protocol [2,15]

Landmark Trial: Stupp et al., NEJM 2005—addition of temozolomide to radiotherapy increased median OS from 12.1 to 14.6 months and 2-year survival from 10% to 26%. [2]

Concurrent Phase (Weeks 1-6):

• Temozolomide: 75 mg/m² daily (including weekends) during radiotherapy
• Antiemetic Prophylaxis: 5-HT3 antagonist (ondansetron) for nausea
• Pneumocystis jirovecii Pneumonia (PJP) Prophylaxis: Trimethoprim-sulfamethoxazole (co-trimoxazole) double strength 3 times weekly during concurrent phase (lymphopenia risk)

Rest Period: 4 weeks

Adjuvant Phase (6 cycles):

• Temozolomide: 150-200 mg/m² daily for 5 consecutive days per 28-day cycle
  • "Cycle 1: 150 mg/m² (if tolerated)"
  • "Cycles 2-6: 200 mg/m² (dose escalation if no significant toxicity)"
• Monitoring: FBC, LFTs weekly initially, then before each cycle

Toxicity:

• Hematologic: Thrombocytopenia (20-30%), lymphopenia (universal, severe in 40-55%), neutropenia
• Non-hematologic: Nausea/vomiting (mild), fatigue, constipation, rash
• Dose Modifications: Hold for ANC less than 1.5, platelets less than 100; reduce dose 50-100 mg/m² for persistent Grade 3-4 toxicity

MGMT Methylation and Temozolomide: [6,7]

• Patients with MGMT promoter methylation have significantly better outcomes with temozolomide (median OS 21.7 months) compared to unmethylated (12.7 months)
• Unmethylated patients still derive some benefit from temozolomide (still superior to radiotherapy alone)

Tumor Treating Fields (TTFields)

Optune Device: Wearable device delivering low-intensity (1-3 V/cm), intermediate-frequency (200 kHz) alternating electric fields to the brain. [18]

Mechanism: Disrupts mitotic spindle formation and cytokinesis, inhibiting tumor cell division.

Evidence: EF-14 trial (Stupp et al., JAMA 2015)—TTFields + temozolomide vs temozolomide alone improved median OS from 16.0 to 20.9 months and 5-year survival from 5% to 13%. [18]

Application:

• Worn ≥18 hours/day for maximal benefit
• Transducer arrays applied to shaved scalp
• Requires patient compliance, lifestyle impact

Side Effects: Scalp dermatitis (most common), headache

Limitations: Cost (~$20,000 per month), inconvenience, not universally available

Emerging Therapies

Bevacizumab (anti-VEGF monoclonal antibody):

• Recurrent GBM: FDA-approved, reduces contrast enhancement and edema, improves PFS but NOT OS
• Newly Diagnosed GBM: AVAglio and RTOG 0825 trials showed improved PFS but no OS benefit; increased toxicity (hypertension, thrombosis, GI perforation, wound healing complications)

Immunotherapy:

• Checkpoint Inhibitors (nivolumab, pembrolizumab): Disappointing results in CheckMate 143, CheckMate 498 trials—no OS benefit
• Vaccines (rindopepimut/EGFRvIII peptide vaccine): ACT IV trial negative
• CAR-T Therapy: Early-phase trials ongoing

Targeted Therapies:

• EGFR inhibitors (erlotinib, gefitinib): Ineffective despite high EGFR alteration rates
• IDH1 inhibitors (ivosidenib): For IDH-mutant gliomas, not glioblastoma (IDH-wildtype by definition)

Management of Recurrent Glioblastoma

Recurrence is inevitable (median PFS 6-8 months). Management individualized based on patient factors, prior therapy, and tumor location.

Options:

• Re-resection: If feasible, improves survival in selected patients
• Re-irradiation: Stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HFSRT) for focal recurrence
• Chemotherapy:
  • Rechallenge with temozolomide (dose-dense regimens)
  • Lomustine (CCNU)
  • Bevacizumab (anti-VEGF)
  • Carboplatin
• Clinical Trials: Encouraged for novel therapeutics
• Palliative Care: Quality of life focus, symptom management

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9. Complications

Disease-Related Complications

1. Cerebral Herniation Syndromes

   • Transtentorial Herniation: Uncal herniation (CN III palsy, decreased consciousness, Cushing's triad), central herniation
   • Subfalcine Herniation: Midline shift, ACA infarction
   • Tonsillar Herniation: Cardiorespiratory arrest (coning)
   • Management: Immediate ICP reduction (hyperventilation, hyperosmolar therapy—mannitol 0.5-1 g/kg or hypertonic saline 3%, emergency decompressive surgery)

2. Hydrocephalus

   • Obstructive (tumor obstructing CSF pathways) or communicating (impaired CSF reabsorption)
   • Ventriculoperitoneal (VP) shunt or external ventricular drain (EVD)

3. Seizures

   • Status epilepticus risk
   • Antiepileptic drug management, ICU monitoring

4. Venous Thromboembolism (VTE)

   • Deep vein thrombosis (DVT), pulmonary embolism (PE)
   • Incidence 20-30% without prophylaxis
   • LMWH prophylaxis recommended

5. Hemorrhage

   • Intratumoral hemorrhage (2-5% of glioblastomas)
   • Presents with sudden neurological deterioration

Treatment-Related Complications

1. Surgical Complications

   • New neurological deficits (4-8% permanent)
   • Infection (wound, meningitis, abscess)
   • Hemorrhage (epidural, subdural, intraparenchymal)
   • CSF leak, pseudomeningocele

2. Radiotherapy Complications

   • Acute (during RT): Fatigue, scalp erythema, alopecia (permanent), exacerbation of symptoms
   • Subacute (weeks-months): Pseudoprogression (20-30%), somnolence syndrome
   • Late (months-years): Radiation necrosis (5-10%), leukoencephalopathy, cognitive decline, pituitary dysfunction, vascular injury (moyamoya syndrome, stroke), secondary malignancies (rare, latency 10-30 years)

3. Temozolomide Toxicity

   • Myelosuppression: Thrombocytopenia, neutropenia, lymphopenia (persistent, PJP risk)
   • Hepatotoxicity: Transaminitis (monitor LFTs)
   • Nausea/Vomiting: Usually mild, manageable with antiemetics
   • Fatigue: Common

4. Corticosteroid Toxicity (prolonged use)

   • Hyperglycemia/steroid-induced diabetes
   • Myopathy (proximal muscle weakness)
   • Psychiatric effects (insomnia, mood changes, psychosis)
   • Cushing's syndrome
   • Immunosuppression (PJP, fungal infections)
   • GI bleeding, peptic ulcers
   • Osteoporosis, avascular necrosis
   • Adrenal suppression (requires gradual taper)

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10. Prognosis and Outcomes

Overall Survival

• Median Overall Survival: 14-15 months with standard Stupp protocol [2,3]
• 1-Year Survival: Approximately 60%
• 2-Year Survival: Approximately 25-30%
• 5-Year Survival: less than 5-7% [3]
• Without Treatment: Median OS 3-4 months

Prognostic Factors

Favorable Prognostic Factors:

1. Younger Age: Age less than 50 associated with better outcomes
2. Good Performance Status: Karnofsky Performance Scale (KPS) ≥70 or ECOG 0-1
3. Extent of Resection: Gross total resection (> 98-99% resection) vs subtotal [17]
4. MGMT Promoter Methylation: Median OS 21.7 months vs 12.7 months for unmethylated [6,7]
5. IDH Mutation: IDH-mutant grade 4 astrocytomas (formerly "secondary GBM") have median OS 24-31 months vs 12-15 months for IDH-wildtype glioblastoma
6. Smaller Tumor Size: less than 5 cm diameter
7. Single Lesion: Multifocal disease portends worse prognosis

Adverse Prognostic Factors:

• Older age (especially > 70 years)
• Poor performance status (KPS less than 70)
• Biopsy only (no resection)
• Large tumor size, multifocal/butterfly configuration
• MGMT unmethylated
• IDH-wildtype

Recursive Partitioning Analysis (RPA) Classification

RTOG/EORTC RPA Classes (based on age, KPS, extent of resection, neurological function): [19]

Patterns of Recurrence

• Local Recurrence (80-90%): Within 2-3 cm of original tumor bed
• Distant Recurrence (less than 10%): New lesion distant from original site
• Median Time to Progression: 6-8 months

Long-Term Survivors

Approximately 2-5% of patients survive > 5 years ("long-term survivors"). Characteristics often include:

• Younger age
• Good performance status
• IDH-mutant (now classified as astrocytoma, IDH-mutant, grade 4)
• MGMT methylated
• Gross total resection
• Good response to initial therapy

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11. Prevention and Screening

Primary Prevention

No Established Primary Prevention due to unclear etiology for the vast majority of cases.

Potential Measures:

• Minimize unnecessary ionizing radiation exposure (only proven environmental risk factor)
• Genetic counseling and surveillance for hereditary cancer syndromes (NF1, Li-Fraumeni, Lynch syndrome)—though these account for less than 5% of cases

Screening

No Routine Screening Recommended for the general population.

Surveillance for High-Risk Individuals (hereditary syndromes):

• Periodic brain MRI screening may be considered for patients with Li-Fraumeni syndrome or other high-risk genetic syndromes, though evidence for benefit is limited

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12. Evidence and Guidelines

Key Guidelines

Landmark Trials and Papers

1. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. [2]

• Comparison: RT alone vs RT + concurrent/adjuvant temozolomide
• Findings: Addition of TMZ increased median OS from 12.1 to 14.6 months; 2-year survival from 10% to 26%
• Impact: Established global standard of care ("Stupp Protocol")

2. Hegi ME, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. [6]

• Findings: MGMT promoter methylation associated with improved response to temozolomide (median OS 21.7 months vs 12.7 months in unmethylated)
• Impact: Established MGMT testing as essential prognostic and predictive biomarker

3. Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466. [7]

• Findings: 5-year survival 9.8% with TMZ vs 1.9% with RT alone
• Impact: Confirmed durable benefit of temozolomide

4. Stupp R, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535-2543. [18]

• Comparison: TTFields + TMZ vs TMZ alone (EF-14 trial)
• Findings: Median OS 20.9 vs 16.0 months; 5-year survival 13% vs 5%
• Impact: FDA approval of TTFields, though adoption limited by cost and inconvenience

5. Louis DN, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. [4]

• Impact: Paradigm shift to molecular classification; IDH-wildtype required for glioblastoma diagnosis

6. Stummer W, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401. [8]

• Findings: 5-ALA increased complete resection rates (65% vs 36%) and 6-month PFS (41% vs 21%)
• Impact: Established 5-ALA fluorescence-guided surgery

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13. Patient and Layperson Explanation

What is Glioblastoma?

Glioblastoma is a very aggressive type of brain cancer. It grows quickly and spreads "roots" or "tentacles" into the surrounding healthy brain tissue. This makes it impossible to remove the tumor completely with surgery without damaging important brain tissue that controls movement, speech, memory, and other vital functions.

Why Did This Happen to Me?

In most cases, we don't know why glioblastomas develop. Unlike some cancers, there is usually no identifiable cause. It is not hereditary (your children are not at increased risk), and it is not caused by anything you did or didn't do. The only established risk factor is previous radiation therapy to the head, which accounts for a very small minority of cases.

Is Glioblastoma Curable?

Currently, glioblastoma is not curable with available treatments. However, treatment can extend life and maintain quality of life for as long as possible. The goal is to shrink the tumor, slow its growth, relieve symptoms, and help you remain as functional and comfortable as possible.

What is the Treatment Plan?

The standard treatment involves three steps:

1. Surgery: The neurosurgeon will remove as much of the tumor as safely possible. The goal is to remove the bulk of the tumor without causing new problems like weakness, speech difficulty, or other neurological issues.

2. Radiotherapy + Chemotherapy (6 weeks): After you recover from surgery, you will have radiation therapy to the brain (5 days per week for 6 weeks) combined with a daily chemotherapy tablet called temozolomide. This combination has been shown to improve survival.

3. Chemotherapy Alone (6 months): After completing radiotherapy, you will continue taking temozolomide tablets for 5 days every month for 6 months.

Throughout treatment, you may need steroids (dexamethasone) to reduce brain swelling and control symptoms.

What About Side Effects?

Surgery: You may experience temporary worsening of symptoms, fatigue, headaches, and risk of infection or bleeding (small risk).

Radiotherapy: Hair loss in the treated area (usually permanent), fatigue, skin redness on the scalp, temporary worsening of symptoms.

Chemotherapy: Nausea (usually mild), fatigue, low blood counts (requiring monitoring with blood tests), increased infection risk.

Steroids: Increased appetite, weight gain, high blood sugar, mood changes, muscle weakness, insomnia.

How Long Will I Live?

This is the most difficult question. On average, patients with glioblastoma treated with surgery and chemotherapy/radiotherapy live approximately 12-18 months. However, this is an average—some patients live shorter, and some live significantly longer (several years). Factors that influence survival include your age, overall health, how much of the tumor can be removed, and certain molecular features of the tumor (MGMT methylation status, which your doctor will test).

Can I Drive?

No. You must inform the DVLA (UK) or equivalent authority immediately and surrender your driving license. The law prohibits driving for at least 12 months after a brain tumor diagnosis due to the high risk of seizures and neurological symptoms that could cause accidents. In practice, most patients with glioblastoma do not regain eligibility to drive due to the progressive nature of the disease.

Can I Work?

This depends on your symptoms, treatment schedule, and the nature of your work. Many patients cannot work during active treatment due to fatigue and treatment appointments. Discuss with your medical team and consider occupational health review and statutory sick pay/disability benefits.

What Happens Next?

After completing treatment, you will have regular brain scans (MRI) every 2-4 months to monitor for tumor recurrence. Unfortunately, glioblastomas almost always come back despite treatment. When recurrence occurs, your medical team will discuss options, which may include more surgery, additional chemotherapy, or enrollment in clinical trials. At any stage, palliative care and supportive care teams are available to help manage symptoms and maintain quality of life.

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14. Examination Focus

Common Exam Questions

1. Histopathology Viva

• "What are the diagnostic histological features of glioblastoma?"
  • "Answer: Pseudopalisading necrosis and microvascular proliferation. Additional features include high cellularity, nuclear pleomorphism, high mitotic activity, and infiltrative growth pattern."

2. Molecular Pathology

• "What is the significance of MGMT promoter methylation in glioblastoma?"
  • "Answer: MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme. Methylation of the MGMT promoter silences the gene, preventing the tumor from repairing DNA damage caused by alkylating chemotherapy agents like temozolomide. MGMT methylation is associated with better response to temozolomide and improved survival (median OS 21.7 months vs 12.7 months in unmethylated tumors). [6,7]"

3. Classification

• "How has the 2021 WHO classification changed the diagnosis of glioblastoma?"
  • Answer: The 2021 WHO CNS5 classification requires IDH-wildtype status for glioblastoma diagnosis. Tumors previously called "secondary glioblastoma" (IDH-mutant) are now classified as "Astrocytoma, IDH-mutant, Grade 4" and have better prognosis. This represents a shift from pure histology to integrated histo-molecular diagnosis. [4]

4. Radiology

• "Describe the typical MRI appearance of glioblastoma."
  • Answer: Irregular, thick ring-enhancing mass with central necrosis on T1-weighted post-gadolinium images. Extensive surrounding T2/FLAIR hyperintense vasogenic edema. Mass effect with midline shift. Infiltrative, irregular margins. May cross corpus callosum ("butterfly glioma").

5. Management

• "What is the Stupp Protocol?"
  • "Answer: Standard treatment for newly diagnosed glioblastoma in fit patients. Consists of maximal safe surgical resection followed by concurrent chemoradiotherapy (60 Gy radiotherapy in 30 fractions over 6 weeks with daily temozolomide 75 mg/m²) followed by adjuvant temozolomide (150-200 mg/m² days 1-5 of 28-day cycles for 6 cycles). Established by Stupp et al. NEJM 2005 trial, which showed improved median OS from 12.1 to 14.6 months. [2]"

6. Surgical Adjuncts

• "What is 5-ALA and how does it improve glioblastoma surgery?"
  • "Answer: 5-Aminolevulinic acid (5-ALA) is a prodrug given orally pre-operatively. Metabolized to protoporphyrin IX, which accumulates in glioblastoma cells. Under blue-violet light (400-410 nm), tumor cells fluoresce bright pink, improving visualization of tumor margins. Randomized trial showed increased complete resection rates (65% vs 36%) and improved 6-month PFS (41% vs 21%). [8]"

Viva Points and Model Answers

Opening Statement for Glioblastoma:

"Glioblastoma is the most common and most aggressive primary malignant brain tumor in adults, classified as WHO Grade 4 astrocytoma. It is defined by IDH-wildtype status per the 2021 WHO classification and characterized histologically by pseudopalisading necrosis and microvascular proliferation. Despite maximal therapy with surgery, radiotherapy, and temozolomide chemotherapy, median survival is approximately 14-15 months due to its highly infiltrative nature and inevitable recurrence."

Key Points to Hit:

• Epidemiology: Median age 64, M>F 1.6:1, incidence 3-4 per 100,000
• Molecular: IDH-wildtype required; MGMT methylation predicts temozolomide response
• Imaging: Irregular ring-enhancing mass with necrosis, extensive edema
• Histology: Pseudopalisading necrosis + microvascular proliferation
• Management: Stupp protocol (surgery → concurrent chemoRT → adjuvant TMZ)
• Prognosis: Median OS 14-15 months; 5-year survival less than 5%

Pseudoprogression:

"What is pseudoprogression and how do you distinguish it from true tumor progression?"

Answer: Pseudoprogression is a treatment-related phenomenon occurring in approximately 20-30% of glioblastoma patients within 3 months of completing chemoradiotherapy. It manifests as increased contrast enhancement and edema on MRI, mimicking tumor progression, but represents treatment-induced inflammation and necrosis rather than viable tumor growth. Distinguishing features include:

• Timing: Typically within 12 weeks of completing RT
• Clinical Stability: Patients often clinically stable or improving despite worsening imaging
• Imaging Evolution: Tends to stabilize or improve on subsequent scans without treatment change
• Advanced Imaging:
  • Perfusion MRI shows low relative cerebral blood volume (rCBV) in pseudoprogression vs high in true progression
  • Amino acid PET (18F-FET, 11C-methionine) shows low uptake in pseudoprogression
• Histology: Biopsy (if performed) shows treatment effect, necrosis, inflammation without viable tumor

Management is supportive with steroids and watchful waiting. True progression requires treatment modification.

MGMT Biology Deep Dive:

"Explain the mechanism by which MGMT methylation predicts temozolomide response."

Answer: MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine residues. Temozolomide is a prodrug that spontaneously converts to the active metabolite MTIC (monomethyl triazeno imidazole carboxamide), which methylates DNA at the O6 position of guanine, causing DNA mispairs (O6-methylguanine pairs with thymine instead of cytosine). This triggers futile mismatch repair cycles, leading to DNA double-strand breaks and apoptosis.

When the MGMT promoter is methylated (epigenetic silencing via CpG island methylation), the MGMT enzyme is not expressed. Tumor cells cannot repair the O6-methylguanine lesions, making them highly sensitive to temozolomide-induced cytotoxicity. Conversely, unmethylated MGMT promoter results in high MGMT expression, enabling efficient repair of temozolomide-induced DNA damage and resistance.

MGMT promoter methylation occurs in ~40-45% of glioblastomas and is associated with median OS of 21.7 months vs 12.7 months in unmethylated tumors treated with the Stupp protocol. [6,7]

Common Mistakes to Avoid

❌ Calling it "Glioblastoma Multiforme": The term "multiforme" has been dropped in modern nomenclature. Use "glioblastoma" or "glioblastoma, IDH-wildtype."

❌ Failing to mention IDH status: Under WHO 2021, IDH-wildtype status is REQUIRED for glioblastoma diagnosis. Always state "IDH-wildtype glioblastoma."

❌ Confusing MGMT biology: MGMT methylation (good prognosis) means the gene is SILENCED (not expressed), so the tumor CANNOT repair DNA damage from temozolomide, making it SENSITIVE to chemotherapy. This is counterintuitive—methylation silences a protective mechanism.

❌ Overstating survival: Avoid giving false hope. Median OS is 14-15 months; 5-year survival less than 5%. This is an aggressive, incurable disease with current therapies.

❌ Prophylactic antiepileptics: NOT recommended routinely. Only treat seizures that have occurred. [16]

❌ Missing red flags: New seizure, progressive headache, focal deficit in adults mandate urgent imaging. Don't delay.

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15. References

1. Ostrom QT, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013-2017. Neuro Oncol. 2020;22(12 Suppl 2):iv1-iv96. doi:10.1093/neuonc/noaa200

2. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330

3. Melhem JM, et al. Updates in IDH-Wildtype Glioblastoma. Neurotherapeutics. 2022;19(6):1705-1723. doi:10.1007/s13311-022-01251-6

4. Louis DN, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106

5. Śledzińska P, et al. Prognostic and Predictive Biomarkers in Gliomas. Int J Mol Sci. 2021;22(19):10373. doi:10.3390/ijms221910373

6. Hegi ME, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. doi:10.1056/NEJMoa043331

7. Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466. doi:10.1016/S1470-2045(09)70025-7

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

9. Guo X, et al. Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors. Front Oncol. 2023;13:1200815. doi:10.3389/fonc.2023.1200815

10. Ostrom QT, et al. Epidemiology of Intracranial Gliomas. Prog Neurol Surg. 2018;30:1-11. doi:10.1159/000464374

11. Brenner AV, et al. History of cancer radiotherapy and risk of brain tumours in adults: cohort and case-control studies. Radiat Res. 2014;181(3):279-292. doi:10.1667/RR13449.1

12. INTERPHONE Study Group. Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case-control study. Int J Epidemiol. 2010;39(3):675-694. doi:10.1093/ije/dyq079

13. Johnson DR, et al. Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of imaging in the management of progressive glioblastoma in adults. J Neurooncol. 2022;158(2):139-165. doi:10.1007/s11060-021-03853-0

14. Farrell C, et al. Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of emerging developments in the management of newly diagnosed glioblastoma. J Neurooncol. 2020;150(2):269-359. doi:10.1007/s11060-020-03607-4

15. Mohile NA, et al. Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline. J Clin Oncol. 2022;40(4):403-426. doi:10.1200/JCO.21.02036

16. Glantz MJ, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(10):1886-1893. doi:10.1212/wnl.54.10.1886

17. Sanai N, et al. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3-8. doi:10.3171/2011.2.JNS10998

18. Stupp R, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535-2543. doi:10.1001/jama.2015.16669

19. Scott JG, et al. Recursive partitioning analysis of prognostic variables in glioblastoma patients treated with chemoradiotherapy. Br J Radiol. 2012;85(1018):e1130-e1137. doi:10.1259/bjr/24498385

20. National Institute for Health and Care Excellence. Brain tumours (primary) and brain metastases in adults. NICE Guideline NG99. 2018. Available at: https://www.nice.org.uk/guidance/ng99

21. Weller M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170-186. doi:10.1038/s41571-020-00447-z

22. Germano IM, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Management of Progressive Glioblastoma in Adults: Update of the 2014 Guidelines. Neurosurgery. 2022;90(5):e112-e115. doi:10.1227/neu.0000000000001903

23. Redjal N, et al. Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults. J Neurooncol. 2020;150(2):165-213. doi:10.1007/s11060-020-03601-w

24. Chen Y, et al. MGMT promoter methylation and glioblastoma prognosis: a systematic review and meta-analysis. Arch Med Res. 2013;44(4):281-290. doi:10.1016/j.arcmed.2013.04.004

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and current guidelines.