🧬 Understanding GBM Types

Different molecular profiles = different prognosis and treatment response

Months median survival

5-year survival rate

Key molecular markers

🔬 Key Molecular Markers

Not all GBMs are the same. Three key markers dramatically affect prognosis:

1. MGMT Methylation Status

What is it?

MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme. When the MGMT gene is methylated (silenced), the tumor cannot repair damage from temozolomide chemotherapy.

Status	% of Patients	TMZ Response	Median Survival
MGMT Methylated	35-45%	✓ Good response	21-23 months
MGMT Unmethylated	55-65%	✗ Poor response	12-15 months

Key insight: If MGMT unmethylated, TMZ provides minimal benefit. Alternative approaches (immunotherapy, TTFields, clinical trials) become more important.

2. IDH Mutation Status

What is it?

IDH (Isocitrate Dehydrogenase) mutations are found in some brain tumors. IDH-mutant tumors have a significantly better prognosis.

Status	% of GBM	Prognosis	Median Survival
IDH-Mutant (Grade 4 Astrocytoma)	~10%	Better	31-38 months
IDH-Wildtype (True GBM)	~90%	Worse	14-16 months

Note: Since 2021 WHO classification, IDH-mutant grade 4 tumors are no longer called "GBM" — they're "Astrocytoma, IDH-mutant, Grade 4". True GBM is always IDH-wildtype.

3. 1p/19q Co-deletion

What is it?

Loss of parts of chromosomes 1 and 19. This is characteristic of oligodendrogliomas, not true GBM.

Status	Tumor Type	Prognosis
1p/19q Co-deleted	Oligodendroglioma	Much better (years)
1p/19q Intact	Astrocytoma/GBM	Standard GBM prognosis

📊 Molecular Subtypes of GBM

Beyond the key markers, GBM can be classified into molecular subtypes based on gene expression:

Subtype	% of Cases	Characteristics	Prognosis
Classical	~25%	EGFR amplification, no p53 mutation	Moderate
Mesenchymal	~30%	NF1 mutations, inflammatory	Worst prognosis
Proneural	~30%	PDGFRA alterations, younger patients	Better (if IDH-mutant)
Neural	~15%	Normal brain gene expression	Variable

⚠️ Important: These subtypes can change during treatment and recurrence. A tumor may shift from Proneural to Mesenchymal after radiation, which is associated with worse outcomes.

📈 Treatment Response by Profile

Best Case Scenario

IDH-Mutant + MGMT Methylated

Median survival: 31+ months
5-year survival: ~20%
Responds well to TMZ
Often younger patients

Average Case

IDH-Wildtype + MGMT Methylated

Median survival: 21-23 months
5-year survival: ~10%
Good TMZ response
Standard Stupp protocol effective

Worst Case Scenario

IDH-Wildtype + MGMT Unmethylated

Median survival: 12-14 months
5-year survival: <5%
Poor TMZ response — consider alternatives
Clinical trials, TTFields more important

🏥 Standard Treatment Protocol (Stupp Protocol)

The Stupp Protocol, established in 2005, remains the standard of care for newly diagnosed GBM. Named after Dr. Roger Stupp who led the pivotal trial.

Phase 1: Surgery (Day 0)

Goal: Remove as much tumor as safely possible

Gross Total Resection (GTR) — Remove >95% of tumor. Best outcomes.
Subtotal Resection — Partial removal if near critical areas
Biopsy only — If surgery too risky (deep/critical location)

Extent of resection is one of the strongest prognostic factors.

Phase 2: Concurrent Chemoradiation (Weeks 1-6)

Duration: 6 weeks, daily (Monday-Friday)

Radiation: 60 Gy total, delivered in 30 fractions (2 Gy/day)
Temozolomide (TMZ): 75 mg/m² daily during radiation
Given together — TMZ sensitizes tumor to radiation

Phase 3: Rest Period (4 weeks)

Recovery break between concurrent and adjuvant phase

Phase 4: Adjuvant Temozolomide (6-12 months)

Schedule: 5 days on, 23 days off (28-day cycles)

Cycle 1: 150 mg/m²/day × 5 days
Cycles 2-6+: 200 mg/m²/day × 5 days (if tolerated)
Minimum 6 cycles, sometimes extended to 12

Phase 5: Monitoring

MRI every 2-3 months to check for recurrence

Additional Treatment Options

Tumor Treating Fields (TTFields / Optune)

Added to Stupp Protocol in 2015

Device worn on shaved head 18+ hours/day
Delivers alternating electric fields
Disrupts cancer cell division
Adds ~5 months to median survival
FDA approved for newly diagnosed GBM

Survival with TTFields: Median 20.9 months (vs 16 without)

Bevacizumab (Avastin)

Anti-angiogenic (blocks VEGF)
Often used at recurrence
Improves symptoms but not overall survival
Reduces brain swelling

CCNU (Lomustine)

Alternative chemotherapy
Sometimes combined with TMZ (CeTeG trial)
Option for MGMT methylated patients

📉 Why Standard Treatment Often Fails

Problem	Explanation
Infiltrative growth	GBM cells spread into healthy brain — surgery can never remove all
Blood-brain barrier	Most chemotherapies can't reach tumor effectively
Tumor heterogeneity	Different cells within tumor respond differently to treatment
Cancer stem cells	Treatment-resistant cells survive and regrow tumor
Immunosuppressive	GBM actively suppresses immune system in brain
Rapid adaptation	Tumor evolves resistance during treatment

🔄 At Recurrence

Almost all GBMs recur. Options at recurrence include:

Re-resection — If surgically accessible
Re-irradiation — Lower doses, stereotactic
Bevacizumab (Avastin) — Most common
Lomustine (CCNU) — Alternative chemo
Clinical trials — Often best option
TTFields — If not used initially

💡 Key Takeaway

Standard treatment hasn't changed much since 2005. If you have poor prognostic markers (IDH-wildtype, MGMT unmethylated), strongly consider:

Adding TTFields (Optune)
Clinical trials for immunotherapy
Complementary approaches (metabolic, natural compounds)

Don't just accept "standard treatment" — advocate for additions.

📋 Questions for Your Oncologist

"What is my MGMT methylation status?" — Critical for TMZ response
"Is my tumor IDH-mutant or wildtype?" — Major prognostic factor
"What was the extent of resection?" — GTR vs subtotal
"Am I a candidate for TTFields?" — Adds survival
"What clinical trials am I eligible for?" — Often best options
"What happens when/if it recurs?" — Plan ahead