Glioblastoma Multiforme

IDH-wildtype grade 4 astrocytoma — MGMT methylation, Stupp protocol, Tumor Treating Fields, and the emerging role of targeted and immunotherapy strategies

Key Points

• Glioblastoma (GBM) is the most common malignant primary brain tumor in adults (~14,490 new cases/year in the US), with a median overall survival of ~15–16 months despite optimal treatment.
• GBM is defined in the 2021 WHO Classification as IDH-wildtype, grade 4 astrocytoma; IDH-mutant grade 4 tumors are a distinct, more favorable entity.
• MGMT promoter methylation (~40–50% of GBM) predicts benefit from temozolomide chemotherapy and correlates with improved survival (~21–24 vs. 12–15 months).
• Standard treatment (Stupp protocol): maximal safe surgical resection → concurrent temozolomide + 60 Gy RT (6 weeks) → adjuvant temozolomide × 6 cycles.
• Tumor Treating Fields (TTFields/Optune) added to maintenance temozolomide improved median OS from 16.0 to 20.9 months in newly diagnosed GBM (EF-14 trial).
• Bevacizumab is FDA approved for recurrent GBM (extends PFS, no OS benefit); no standard second-line agent exists — clinical trial enrollment is strongly encouraged.
• Ionizing radiation is the only established environmental risk factor; no convincing evidence links cell phone use to GBM.

Epidemiology & WHO Classification

Glioblastoma is the most common and most lethal primary malignant brain tumor in adults, accounting for approximately 47% of all malignant primary brain and CNS tumors. In 2024, approximately 14,490 new cases were projected in the United States, with ~10,000 deaths annually. The median age at diagnosis is 65 years; GBM is rare before age 40. The prognosis remains dismal despite decades of research — fewer than 10% of patients survive 5 years, and the median overall survival with optimal therapy is approximately 15–16 months. The 2021 WHO Classification of CNS Tumors made a fundamental…

Molecular Biology & Biomarkers

Key molecular markers in GBM that have prognostic and/or predictive significance: MGMT promoter methylation (~40–50% of IDH-wildtype GBM): • The MGMT gene encodes O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that removes alkyl adducts from O6-guanine — the primary cytotoxic lesion caused by temozolomide. • When the MGMT promoter is methylated, MGMT expression is silenced → tumor cells cannot repair TMZ-induced DNA damage → enhanced cell death. • MGMT methylation is the strongest predictive biomarker for TMZ benefit (EORTC 26981/NCIC CE.3 — Hegi, 2005): methylated patients had…

Clinical Presentation & Diagnosis

GBM presents with symptoms reflecting mass effect, cerebral edema, and infiltration of eloquent brain regions. The clinical course is often rapid — symptoms typically evolve over weeks to 2–3 months: Common presenting features: • Headache (~50%): Often morning headache, positional, aggravated by Valsalva — classic features of elevated intracranial pressure (ICP). However, GBM headache is often non-specific and may not have classic ICP characteristics. • New-onset seizures (~25–30%): GBM is the most common cause of new seizures in adults over 50. Any adult with a new unprovoked seizure should…

Standard Treatment (Stupp Protocol)

The Stupp protocol, established in the landmark EORTC 26981/NCIC CE.3 randomized trial (2005, updated 2009), remains the standard of care for newly diagnosed GBM in patients with good performance status: Step 1 — Maximal safe surgical resection: • Extent of resection (EOR) is independently associated with improved OS — gross total resection (GTR, 65–70) or poor PS: Hypofractionated RT (40 Gy/15 fractions or 25 Gy/5 fractions) ± TMZ. • Temozolomide (TMZ) 75 mg/m² orally daily (including weekends) throughout RT: 42 days total. PCP prophylaxis (TMP-SMX) required during concurrent phase. Step 3…

Recurrent GBM & Emerging Therapies

Nearly all GBMs recur, typically within 6–10 months of completing initial treatment. Recurrence is inevitably fatal, with median OS after recurrence of ~6–9 months. No standard second-line treatment has been established: Bevacizumab (Avastin — anti-VEGF): • FDA approved 2009 for recurrent GBM based on two single-arm phase II trials (BRAIN/AVF3708g, NCI 06-C-0064E) showing PFS benefit and steroid-sparing effect. • Phase III trials (AVAglio for 1st-line, BELOB for 2nd-line) failed to demonstrate OS improvement. • Clinical role: Reduces tumor-related edema (steroid-sparing), improves quality of…