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GBMDavid Tran
Grand Rounds 1/9/09
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No disclosures to report
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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 . . .
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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.
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• Craniotomy and subtotal resection of the tumor.
• Path: Glioblastoma Multiforme, WHO Grade IV.
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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.
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Surgical Resection
Median survival with surgery alone: 4-6 months
Extent of surgical resection correlated with survival
J.Neurosurg 2003, 99:467-473
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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)
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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)
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Radiation +/- PCV
J Clin Oncol; 19:509-518 2001
RT+PCV
RT
Grade III + IV
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J Clin Oncol; 19:509-518 2001
PCV has activities against Grade III but not Grade IV Gliomas
Grade III
Grade IV
RT+PVCRT
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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
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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.
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NEJM 2005; 352:987-996
TMZ increases both OS and PFS in GBM treated with Radiotherepy
14.6m
12.1m 26.5%
10.4%
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TMZ is Well Tolerated
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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
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MGMT Promoter Methylation Status is a Prognostic Indicator regardless of Therapy
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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)
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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%
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Vredenburgh, J. J. et al. J Clin Oncol; 25:4722-4729 2007
HOWEVER …
Before
Before
Before
Before
After
After
After
After
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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.
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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.
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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.