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  1. 1. GBM David Tran Grand Rounds 1/9/09
  2. 2. No disclosures to report
  3. 3. 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 . . .
  4. 4. 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.
  5. 5. • Craniotomy and subtotal resection of the tumor. • Path: Glioblastoma Multiforme, WHO Grade IV.
  6. 6. 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.
  7. 7. Surgical Resection Median survival with surgery alone: 4-6 months Extent of surgical resection correlated with survival J.Neurosurg 2003, 99:467-473
  8. 8. 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)
  9. 9. 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)
  10. 10. Radiation +/- PCV J Clin Oncol; 19:509-518 2001 RT+PCV RT Grade III + IV
  11. 11. J Clin Oncol; 19:509-518 2001 PCV has activities against Grade III but not Grade IV Gliomas Grade III Grade IV RT+PVC RT
  12. 12. 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
  13. 13. TMZ in GBMDiagnosis/ Surgery WITH or WITHOUT CONCURRENT 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.
  14. 14. NEJM 2005; 352:987-996 TMZ increases both OS and PFS in GBM treated with Radiotherepy 14.6m 12.1m 26.5% 10.4%
  15. 15. TMZ is Well Tolerated
  16. 16. 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
  17. 17. MGMT Promoter Methylation Status is a Prognostic Indicator regardless of Therapy
  18. 18. Recurrent/Progressive GBM The 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)
  19. 19. 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%
  20. 20. Vredenburgh, J. J. et al. J Clin Oncol; 25:4722-4729 2007 HOWEVER … Before Before Before Before After After After After
  21. 21. 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.
  22. 22. 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.
  23. 23. 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.