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  1. 1. Glioblastoma MultiformeGlioblastoma Multiforme Treatment OptionsTreatment Options
  2. 2. Patient HistoryPatient History ►47 y/o female presented with focal motor47 y/o female presented with focal motor seizures involving the face and slurredseizures involving the face and slurred speechspeech ►MRI showed a 1.5 x 2.6 x 2.2cm tumor inMRI showed a 1.5 x 2.6 x 2.2cm tumor in the left frontal lobethe left frontal lobe ►Subtotal excision of the mass withSubtotal excision of the mass with pathology positive for glioblastomapathology positive for glioblastoma multiformemultiforme
  3. 3. Primary Intracranial CNS TumorsPrimary Intracranial CNS Tumors ►Gliomas (46%)Gliomas (46%)  Astrocytomas (40%)Astrocytomas (40%)  Oligodendrogliomas (5%)Oligodendrogliomas (5%)  Mixed Oligoastrocytomas (1%)Mixed Oligoastrocytomas (1%) ►Meningiomas (27%)Meningiomas (27%) ►Pituitary (9.7%)Pituitary (9.7%) ►Nerve sheath (7.3%)Nerve sheath (7.3%) ►CNS lymphoma (3.5%)CNS lymphoma (3.5%) ►Craniopharyngiomas (1.0%)Craniopharyngiomas (1.0%) ►Other (5%)Other (5%)
  4. 4. GliomasGliomas ► AstrocytomasAstrocytomas  Pilocytic Astrocytomas (grade 1)Pilocytic Astrocytomas (grade 1)  Diffuse Astrocytomas (grade 2)Diffuse Astrocytomas (grade 2)  Anaplastic Astrocytomas (grade 3)Anaplastic Astrocytomas (grade 3)  Glioblastoma Multiforme (grade 4 – 50%)Glioblastoma Multiforme (grade 4 – 50%) ► OligodendrogliomasOligodendrogliomas  Low Grade Oligodendroglioma (grade 2)Low Grade Oligodendroglioma (grade 2)  Anaplastic Oligodendroglioma (grade 3)Anaplastic Oligodendroglioma (grade 3) ► Mixed OligoastrocytomasMixed Oligoastrocytomas  Low Grade Oligoastrocytoma (grade 2)Low Grade Oligoastrocytoma (grade 2)  Anaplastic Oligodendroglioma (grade 3)Anaplastic Oligodendroglioma (grade 3)
  5. 5. Clinical PresentationClinical Presentation ►Symptoms caused by mass effect orSymptoms caused by mass effect or destruction of normal tissuedestruction of normal tissue ►SymptomsSymptoms  HeadacheHeadache  SeizuresSeizures  Neurological DeficitsNeurological Deficits ►Personality ChangesPersonality Changes ►Slowing of Motor Function/HemiplegiaSlowing of Motor Function/Hemiplegia ►HallucinationsHallucinations ►Memory ImpairmentMemory Impairment ►Vision ImpairmentVision Impairment
  6. 6. Prognosis for GBMPrognosis for GBM ►Mean survival 12-14 months from diagnosisMean survival 12-14 months from diagnosis ►Mean survival 4-5 months from recurrenceMean survival 4-5 months from recurrence ►2 year survival 10%2 year survival 10% ►Recurrence occurs within 2-3 cm of theRecurrence occurs within 2-3 cm of the margins of the original tumor in 80% ofmargins of the original tumor in 80% of patientspatients
  7. 7. Prognostic Factors in GBMPrognostic Factors in GBM ►AgeAge ►Performance statusPerformance status ►Neurologic functional statusNeurologic functional status
  8. 8. TreatmentTreatment ►SurgerySurgery ►RadiationRadiation ►ChemotherapyChemotherapy
  9. 9. Treatment - SurgeryTreatment - Surgery ►Surgery done for diagnosis and to relieveSurgery done for diagnosis and to relieve symptoms when possiblesymptoms when possible ►Median survival after surgery alone is 3-4Median survival after surgery alone is 3-4 monthsmonths ►Resections are suboptimal secondary toResections are suboptimal secondary to preservation of normal brain tissuepreservation of normal brain tissue ►Re-excision at recurrence an option inRe-excision at recurrence an option in patients with good performance statuspatients with good performance status
  10. 10. Treatment - RadiationTreatment - Radiation ►Radiation after surgery extends medianRadiation after surgery extends median survival to 9-11 monthssurvival to 9-11 months ►CNS tumors infiltrate into surroundingCNS tumors infiltrate into surrounding normal brain tissue up to 3 cm or morenormal brain tissue up to 3 cm or more ►Radiation delivered on a focal field includingRadiation delivered on a focal field including the tumor bed with a 2-3 cm margin withthe tumor bed with a 2-3 cm margin with total dose of 58-60 Gytotal dose of 58-60 Gy
  11. 11. Treatment - ChemotherapyTreatment - Chemotherapy ►Nitrosoureas (BCNU/CCNU)Nitrosoureas (BCNU/CCNU)  Best known chemotherapy agentsBest known chemotherapy agents  Metaanalysis showed increase in medianMetaanalysis showed increase in median survival of 2 months over surgery and radiationsurvival of 2 months over surgery and radiation alonealone  BCNU impregnated wafers show similar resultsBCNU impregnated wafers show similar results to systemic therapyto systemic therapy ►PVC (Procarbazine, CCNU,PVC (Procarbazine, CCNU, Vincristine)Vincristine)
  12. 12. ►TemozolomideTemozolomide  Oral alkylating agentOral alkylating agent  Randomized Controlled Trial in patients (225) withRandomized Controlled Trial in patients (225) with relapse GBM +/- prior chemotherapyrelapse GBM +/- prior chemotherapy ProcarbazineProcarbazine TemozolomideTemozolomide 6 month PFS6 month PFS 8%8% 21%21% Median PFSMedian PFS 8.3 weeks8.3 weeks 12.4 weeks12.4 weeks Temozolomide group had a 6 week median survivalTemozolomide group had a 6 week median survival advantage (not statistically significant)advantage (not statistically significant) (Yung, WK, et al., British J. Cancer 83, (2000), 588-593)(Yung, WK, et al., British J. Cancer 83, (2000), 588-593)
  13. 13. ►ThalidomideThalidomide  GBM overexpress VEGFGBM overexpress VEGF  Thalidomide blocks VEGF inducedThalidomide blocks VEGF induced angiogenesisangiogenesis  Phase 2 uncontrolled trials in patients withPhase 2 uncontrolled trials in patients with recurrent GBM or High Grade Gliomasrecurrent GBM or High Grade Gliomas  Patients (42) treated with 100-500mg/dayPatients (42) treated with 100-500mg/day ►5% partial response5% partial response ►42% had stable disease for >/= 4 weeks42% had stable disease for >/= 4 weeks ►1 year survival from start of Thalidomide was 35%1 year survival from start of Thalidomide was 35% (Marx, GM. et al, J. of Neuro-Oncology, 54, (2001), 31-38)(Marx, GM. et al, J. of Neuro-Oncology, 54, (2001), 31-38)
  14. 14. ►Thalidomide (cont.)Thalidomide (cont.)  Patients (39) treated with 800-1200mg/dayPatients (39) treated with 800-1200mg/day ►6% partial response6% partial response ►6% minor response6% minor response ►33% had stable disease for >/= 8 weeks33% had stable disease for >/= 8 weeks ►1 year survival from start of Thalidomide was 21%1 year survival from start of Thalidomide was 21% (Fine, HA. et al, J. of Clinical Oncology, 18 (4), (2000), 708-715)(Fine, HA. et al, J. of Clinical Oncology, 18 (4), (2000), 708-715)
  15. 15. ►TamoxifenTamoxifen  GBM expresses high levels of PKC activityGBM expresses high levels of PKC activity  In vitroIn vitro glioma cells are sensitive to inhibitors ofglioma cells are sensitive to inhibitors of PKCPKC  Tamoxifen inhibits PKC in glioma cell lines inTamoxifen inhibits PKC in glioma cell lines in micromolar concentrationsmicromolar concentrations  Postulated Tamoxifen acts to inhibit PKCPostulated Tamoxifen acts to inhibit PKC activityactivity
  16. 16. ►Tamoxifen (cont.)Tamoxifen (cont.)  Patients (35) treated with high dosePatients (35) treated with high dose tamoxifen(100mg BID – males, 80mg BID –tamoxifen(100mg BID – males, 80mg BID – females)females) ►25% partial response25% partial response ►19% with stable disease19% with stable disease ►Median survival from the start of tamoxifen was 7.2Median survival from the start of tamoxifen was 7.2 monthsmonths  2 Patients with DVT2 Patients with DVT (Couldwell, WT., et al, Clinical Cancer Research, 2, (1996), 619-622)(Couldwell, WT., et al, Clinical Cancer Research, 2, (1996), 619-622)
  17. 17. ►BCNU + O6-BenzylguanineBCNU + O6-Benzylguanine  Nitrosoureas cause damage by alkylating DNA,Nitrosoureas cause damage by alkylating DNA, particularly at O6 position of deoxyguanineparticularly at O6 position of deoxyguanine  O6-alkyl-guanine DNA transferase activity isO6-alkyl-guanine DNA transferase activity is responsible for resistance to nitrosoureasresponsible for resistance to nitrosoureas  O6-Benzylguanine inactivates the enzymeO6-Benzylguanine inactivates the enzyme  Trials ongoing looking at combination BCNU +Trials ongoing looking at combination BCNU + O6-BenzylguaineO6-Benzylguaine
  18. 18. ►Phase 1 trial of BCNU + O6-BenzylguaninePhase 1 trial of BCNU + O6-Benzylguanine  Identified the MTD of BCNU combined withIdentified the MTD of BCNU combined with 100mg/M2 of O6-Benzylguanine100mg/M2 of O6-Benzylguanine ►Reported 7 of 23 patients had stable disease for >/=Reported 7 of 23 patients had stable disease for >/= to 1 treatment cycleto 1 treatment cycle  Phase 2 and 3 trials ongoingPhase 2 and 3 trials ongoing (Friedman, HS., et al, J. of Clinical Oncology, 18, (2000), 3522-3528)(Friedman, HS., et al, J. of Clinical Oncology, 18, (2000), 3522-3528)
  19. 19. ►Gleevec ??Gleevec ??  Overexpression of PDGFR seen in GBMOverexpression of PDGFR seen in GBM  Gleevec activity seen in animal studiesGleevec activity seen in animal studies  Not studied in humansNot studied in humans
  20. 20. ConclusionsConclusions ►Glioblastoma multiforme continues to haveGlioblastoma multiforme continues to have a dismal prognosisa dismal prognosis ►Significant work has been done to identifySignificant work has been done to identify genetic pathways in glioma progressiongenetic pathways in glioma progression ►Genetic information being used to identifyGenetic information being used to identify targets for therapies and has potential totargets for therapies and has potential to identify chemotherapy responsive tumorsidentify chemotherapy responsive tumors

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