GBM

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GBM

• David Tran
• Grand Rounds 1/9/09

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• No disclosures to report

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GBM GOOGLED
GBM Isle of Man (International Auto
Identification) GBM Glioblastoma
Multiforme GBM Glomerular Basement
Membrane GBM Green Belt Movement GBM Game Boy
Micro (game console) GBM Gay Black
Male GBM Global Business Model GBM GLAST
(Gamma-Ray Large Area Space Telescope) Burst
Monitor (NASA) GBM Gaussian Beam Model GBM Global
Battle Manager GBM Group Billing Master
(insurance) GBM Global Business Market GBM Grupo
Bioquímico de Guatemala SA GBM Geosphere-Biosphere
Model GBM Global Business Machines Etc . . .
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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

• gt50 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, 99467-473
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Adjuvant Radiotherapy

• Introduced in the 1970s
• Fractionated external beam RT 2 Gy / fraction x
  30 fractions
• 1 year survival 3 with surgery alone vs 24
  with postoperative radiation
• Median survival 4 months for surgery alone vs 12
  months for surgery radiation
• (J Neurosurg 1978 49333-343)

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Adjuvant Systemic Chemotherapy Traditionally Felt
to Be of Little Value

• 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 3031323-1329)
• In 2001, the MRC Brain Tumor Working Party
  reported Phase III RCT of Adjuvant PCV
  (Procarbazine, Lomustine, Vincristine) in
  malignant gliomas. (JCO 2001 19509-518)

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Radiation /- PCV
Grade III IV
RTPCV
RT
J Clin Oncol 19509-518 2001
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PCV has activities against Grade III but not
Grade IV Gliomas
RT
RTPVC
Grade III
Grade IV
J Clin Oncol 19509-518 2001
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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
200062585-2597
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TMZ in GBM
Study Design
Diagnosis/ Surgery
TMZ 150 to 200mg/m2 x 5 days / 28 days x 6 cycles
XRT
6 weeks
6 weeks
4 weeks
WITH or WITHOUT CONCURRENT Daily TMZ 75mg/m2
Brain Imaging

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

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TMZ increases both OS and PFS in GBM treated with
Radiotherepy
14.6m
12.1m
26.5
10.4
NEJM 2005 352987-996
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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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(No Transcript)
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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, 62297 Clin. Cancer Res.
  2003, 91399-1405 Nat Med. 2003, 9669-676)

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Phase II Bevacizumab Irinotican in Recurrent GBM
PFS6 46
1yOS 37
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Vredenburgh, J. J. et al. J Clin Oncol
254722-4729 2007
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Before
After
After
Before
Before
After
Before
After
Vredenburgh, J. J. et al. J Clin Oncol
254722-4729 2007
HOWEVER
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Whats 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.