GBMDavid Tran

Grand Rounds 1/9/09

No disclosures to report

GBM GOOGLEDGBM Isle of Man (International Auto Identification)GBM Glioblastoma MultiformeGBM Glomerular Basement MembraneGBM Green Belt MovementGBM Game Boy Micro (game console)GBM Gay Black MaleGBM Global Business ModelGBM GLAST (Gamma-Ray Large Area Space

Telescope) Burst Monitor (NASA)GBM Gaussian Beam ModelGBM Global Battle ManagerGBM Group Billing Master (insurance)GBM Global Business MarketGBM Grupo Bioquímico de Guatemala SAGBM Geosphere-Biosphere ModelGBM Global Business MachinesEtc . . .

Case

• 32 yo newly minted male nephrologist without significant PMH, who lives alone.

• Did not show up to work, did not return consult pages x 24hrs.

• Mother found pt on the living room floor unconscious abnormal movements of eyes, face, arms and legs, and incontinence.

• In ER, rhadomyolysis, ARF.• Head CT without contrast: possible bitemporal edema (?

HSV encephalitis). Treated with steroids, antiepileptics, empiric antiviral therapy and supportive care.

• MS improved.• Brain MRI: A large right temporal lobe mass with rim

enhancement and diffuse edema extending to the left hemisphere.

• Craniotomy and subtotal resection of the tumor.

• Path: Glioblastoma Multiforme, WHO Grade IV.

Glioblastoma Multiforme• >50% of all malignant glioma cases• 8000-10000 cases per year in North America• Peak incidence 45 to 55 years• WHO Grade IV• Diffusely infiltrating, crossing the midline• Common presentations: symptoms of

increased intracranial pressure, seizure, variable focal neurological findings.

• Characteristic radiographic appearances: contrast rim enhancement with significant peritumoral edema causing midline shift and a necrotic core.

Surgical Resection

Median survival with surgery alone: 4-6 months

Extent of surgical resection correlated with survival

J.Neurosurg 2003, 99:467-473

Adjuvant Radiotherapy

1. Introduced in the 1970s

2. Fractionated external beam RT 2 Gy / fraction x 30 fractions

3. 1 year survival: 3% with surgery alone vs 24% with postoperative radiation

4. Median survival: 4 months for surgery alone vs 12 months for surgery + radiation

(J Neurosurg 1978; 49:333-343)

Adjuvant Systemic Chemotherapy Traditionally Felt to Be of Little Value

1. First tried in late 1970s: Walker et al reported no significant differences in OS in malignant gliomas (Grade III and IV) treated with Radiation alone vs Radiation and a Nitrosourea (BCNU or Semustine. (NEJM 1980; 303:1323-1329)

2. In 2001, the MRC Brain Tumor Working Party reported Phase III RCT of Adjuvant PCV (Procarbazine, Lomustine, Vincristine) in malignant gliomas. (JCO 2001; 19:509-518)

Radiation +/- PCV

J Clin Oncol; 19:509-518 2001

RT+PCV

RT

Grade III + IV

J Clin Oncol; 19:509-518 2001

PCV has activities against Grade III but not Grade IV Gliomas

Grade III

Grade IV

RT+PVCRT

The Age of Temozolomide (TMZ)

• Derivative of DTIC• Orally active alkylating agent• 100% oral bioavailability• Does not require metabolic conversion in

the liver to active metabolites; minimally affected by interpatient variation

• Spontaneously converted at physiologic pH to the potent DNA-cross-linking metabolite MTIC

• Excellent penetration of the BBB• Potent antitumor effects on a variety of

tumors both in vitro and in many murine tumor models

• Well-tolerated. Active in Grade III Glioma.

• MGMT can neutralize/repair methylated DNA caused by TMZ

Friedman, H. S. et al. Clin Cancer Res 2000;6:2585-2597

TMZ in GBMD

iag n

o sis

/S

urg

ery

WITH or WITHOUTCONCURRENT

Daily TMZ 75mg/m2

XRT TMZ 150 to 200mg/m2 x 5 days / 28 days x 6 cycles

6 weeks 6 weeks 4 weeks

Brain Imaging

Study Design

•Total 573 new GBM patients from multiple centers•Patient characteristics are equivalent between the 2 arms.

NEJM 2005; 352:987-996

TMZ increases both OS and PFS in GBM treated with Radiotherepy

14.6m

12.1m 26.5%

10.4%

TMZ is Well Tolerated

MGMT Gene Promoter Methylation

• O6-Methylguanine-DNA-methyltransferase repairs the O6-

methylguanine caused by TMZ• MGMT is strongly induced by TMZ and

other alkylating agents• MGMT expression is suppressed by

CpG methylation within its own promoter

MGMT Promoter Methylation Status is a Prognostic Indicator regardless of Therapy

Recurrent/Progressive GBMThe Role of Anti-Angiogenic Agents

• High grade gliomas are highly vascular tumors.

• GBM has a high expression of VEGF.

• Higher expression of VEGF in GBM associated with poorer prognosis.

(J Neurosurg 2003, 62:297; Clin. Cancer Res. 2003, 9:1399-1405; Nat Med. 2003, 9:669-676)

Vredenburgh, J. J. et al. J Clin Oncol; 25:4722-4729 2007

Phase II Bevacizumab + Irinotican in Recurrent GBM

PFS6 46% 1yOS 37%

15%21%

Vredenburgh, J. J. et al. J Clin Oncol; 25:4722-4729 2007

HOWEVER …

Before

Before

Before

Before

After

After

After

After

What’s NEXT?

• EGFR and EGFRvIII on GBM: Single agent EGFR inhibitors have been disappointing.

• Combining EGFR inhibitors and mTOR inhibitors results in unacceptable toxicities.

• Adequate CNS penetration is the Holy Grail in treating CNS tumors.

Summary• GBM is the most common and most aggressive

malignant gliomas.• “Cure” is rare.• More resection is better than less.• Standard adjuvant therapy: XRT with concurrent

TMZ, followed by HD maintenance TMZ x6-12 months. Well-tolerated.

• Bevacizumab-based therapy at first relapse.• No known effective therapy after Bevacizumab.

The Case Patient

• Completed XRT and concurrent TMZ• Post-treatment MRI is pending before starting

maintenance TMZ.• Back to doing renal consults part-time.• Overall doing well . . . For now.