Glioblastoma Glioblastoma Multiforme Treatment Multiforme Treatment

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Patient HistoryPatient History

►47 y/o female presented with focal 47 y/o female presented with focal motor seizures involving the face and motor seizures involving the face and slurred speechslurred speech

►MRI showed a 1.5 x 2.6 x 2.2cm tumor MRI showed a 1.5 x 2.6 x 2.2cm tumor in the left frontal lobein the left frontal lobe

►Subtotal excision of the mass with Subtotal excision of the mass with pathology positive for glioblastoma pathology positive for glioblastoma multiformemultiforme

Primary Intracranial CNS Primary Intracranial CNS TumorsTumors

►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%)

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)

Clinical PresentationClinical Presentation►Symptoms caused by mass effect or Symptoms 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

Prognosis for GBMPrognosis for GBM

►Mean survival 12-14 months from Mean survival 12-14 months from diagnosisdiagnosis

►Mean survival 4-5 months from Mean survival 4-5 months from recurrencerecurrence

►2 year survival 10%2 year survival 10%►Recurrence occurs within 2-3 cm of Recurrence occurs within 2-3 cm of

the margins of the original tumor in the margins of the original tumor in 80% of patients80% of patients

Prognostic Factors in GBMPrognostic Factors in GBM

►AgeAge►Performance status Performance status ►Neurologic functional statusNeurologic functional status

TreatmentTreatment

►SurgerySurgery►RadiationRadiation►ChemotherapyChemotherapy

Treatment - SurgeryTreatment - Surgery

►Surgery done for diagnosis and to Surgery done for diagnosis and to relieve symptoms when possiblerelieve symptoms when possible

►Median survival after surgery alone is Median survival after surgery alone is 3-4 months3-4 months

►Resections are suboptimal secondary Resections are suboptimal secondary to preservation of normal brain tissueto preservation of normal brain tissue

►Re-excision at recurrence an option in Re-excision at recurrence an option in patients with good performance statuspatients with good performance status

Treatment - RadiationTreatment - Radiation

►Radiation after surgery extends Radiation after surgery extends median survival to 9-11 monthsmedian survival to 9-11 months

►CNS tumors infiltrate into surrounding CNS 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 Radiation delivered on a focal field including the tumor bed with a 2-3 cm including the tumor bed with a 2-3 cm margin with total dose of 58-60 Gymargin with total dose of 58-60 Gy

Treatment - ChemotherapyTreatment - Chemotherapy

►Nitrosoureas (BCNU/CCNU)Nitrosoureas (BCNU/CCNU) Best known chemotherapy agentsBest known chemotherapy agents Metaanalysis showed increase in median Metaanalysis showed increase in median

survival of 2 months over surgery and survival of 2 months over surgery and radiation aloneradiation alone

BCNU impregnated wafers show similar BCNU impregnated wafers show similar results to systemic therapyresults to systemic therapy

►PVC (Procarbazine, CCNU, PVC (Procarbazine, CCNU, Vincristine)Vincristine)

►TemozolomideTemozolomide Oral alkylating agentOral alkylating agent Randomized Controlled Trial in patients (225) Randomized Controlled Trial in patients (225)

with relapse GBM +/- prior chemotherapywith relapse GBM +/- prior chemotherapyProcarbazineProcarbazine

TemozolomideTemozolomide6 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 survival Temozolomide 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-(Yung, WK, et al., British J. Cancer 83, (2000), 588-593)593)

►ThalidomideThalidomide GBM overexpress VEGF GBM overexpress VEGF Thalidomide blocks VEGF induced Thalidomide blocks VEGF induced

angiogenesisangiogenesis Phase 2 uncontrolled trials in patients with Phase 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, (Marx, GM. et al, J. of Neuro-Oncology, 54, (2001), 31-38)(2001), 31-38)

►Thalidomide (cont.)Thalidomide (cont.) Patients (39) treated with Patients (39) treated with

800-1200mg/day800-1200mg/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 1 year survival from start of Thalidomide was

21%21%(Fine, HA. et al, J. of Clinical Oncology, 18 (4), (Fine, HA. et al, J. of Clinical Oncology, 18 (4),

(2000), 708-715)(2000), 708-715)

►TamoxifenTamoxifen GBM expresses high levels of PKC activityGBM expresses high levels of PKC activity In vitroIn vitro glioma cells are sensitive to glioma cells are sensitive to

inhibitors of PKCinhibitors of PKC Tamoxifen inhibits PKC in glioma cell lines Tamoxifen inhibits PKC in glioma cell lines

in micromolar concentrationsin micromolar concentrations Postulated Tamoxifen acts to inhibit PKC Postulated Tamoxifen acts to inhibit PKC

activityactivity

►Tamoxifen (cont.)Tamoxifen (cont.) Patients (35) treated with high dose Patients (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 Median survival from the start of tamoxifen

was 7.2 monthswas 7.2 months 2 Patients with DVT2 Patients with DVT

(Couldwell, WT., et al, Clinical Cancer Research, 2, (Couldwell, WT., et al, Clinical Cancer Research, 2, (1996), 619-622)(1996), 619-622)

►BCNU + O6-BenzylguanineBCNU + O6-Benzylguanine Nitrosoureas cause damage by alkylating Nitrosoureas cause damage by alkylating

DNA, particularly at O6 position of DNA, particularly at O6 position of deoxyguaninedeoxyguanine

O6-alkyl-guanine DNA transferase activity O6-alkyl-guanine DNA transferase activity is responsible for resistance to nitrosoureasis responsible 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-Benzylguaine+ O6-Benzylguaine

►Phase 1 trial of BCNU + O6-Phase 1 trial of BCNU + O6-BenzylguanineBenzylguanine Identified the MTD of BCNU combined with Identified the MTD of BCNU combined with

100mg/M2 of O6-Benzylguanine100mg/M2 of O6-Benzylguanine►Reported 7 of 23 patients had stable disease Reported 7 of 23 patients had stable disease

for >/= to 1 treatment cyclefor >/= to 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-(Friedman, HS., et al, J. of Clinical Oncology, 18, (2000), 3522-3528)3528)

►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

ConclusionsConclusions

►Glioblastoma multiforme continues to Glioblastoma multiforme continues to have a dismal prognosishave a dismal prognosis

►Significant work has been done to Significant work has been done to identify genetic pathways in glioma identify genetic pathways in glioma progressionprogression

►Genetic information being used to Genetic information being used to identify targets for therapies and has identify targets for therapies and has potential to identify chemotherapy potential to identify chemotherapy responsive tumorsresponsive tumors