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Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
Brain Tumors (Subramaniam)
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Brain Tumors (Subramaniam)

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  • A third of low grade astrocytomas have mutations in the p53 gene. A similar incidence of these mutations is also seen in anaplatic astros, but 40% of AAs also have LOH 19q and mutations in the Rb gene on Chromosome 13. Much attempt has been made to see what triggers the transformation of AA into a GBM. Interesting EGFR amplification appears to be a hallmark of this transformation in at least a third of GBMs. 70% carry LOH 10q/PTEN mutation.
  • The outer margin of the T2 weighted abnormality on MRI is the most accurate measure of the boundary of the malignant astrocytoma
  • No prospective RCTs to show benefit of surgical resection.
  • Shift from WBRT to focal EBRT as recurrent astrocytoma following WBRT develops within 2 cm of original site in 80-90% of cases**
    MS of 28, 36, and 42 weeks for patients treated with 50, 55, and 60 Gy respectively***
  • Brain Tumor Study Group was formed in 1967; here are a couple of early protocols which showed benefit to adding chemo to radiation
  • The first study to open the door to combination regimens for malignant gliomas; 73 patients with AA, 60 patients with GBM; BCNU and PCV groups were matched for age, KPS, extent of surgical resection; PCV produced a 2-fold increase in TTP and survival at the 50th percentiles for AA, not so for GBM; results disappointing, but considering survival of GBM patients is short, NNT to see benefit is probably much greater; Regimens: BCNU 200 mg/m2 IV; CCNU 110 mg/m2 orally on day1;
    P160 mg/m2 orally on day 8 to 21;
    V 1.4 mg/m2 IV on days 8, 29
  • Unusually poor outcome in AA group (MS: 13 months)
    Lack of correlation between usual prognostic factors and outcome
    Nonstandard dosing schedule:CCNU 100 mg/m2 day 1
    Procarbazine ONLY 100 mg/m2 days 1 to 10
    vincristine 1.5 mg/m2 (max 2 mg) day 1
  • Stable in the low gastric pH
    Very lipophilic
    Active metabolite: MTIC: monomethyl 5-triazeno imidazole carboxamide; methylates the O6 and N7 of guanine,
    with subsequent aberrant repair of the methyl adduct viz. O6-methylguanine;
    Causes DNA breaks rather than chemical cross-linking, hence less myelotoxic
  • Transcript

    • 1. Brain TumorsBrain Tumors Deepa Subramaniam, M.D.Deepa Subramaniam, M.D. Director, Brain Tumor CenterDirector, Brain Tumor Center Lombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center Georgetown University HospitalGeorgetown University Hospital Apr 20, 2009Apr 20, 2009
    • 2. Classification: 1Classification: 1oo CNS TumorsCNS Tumors Glial tumorsGlial tumors Astrocytic:Astrocytic: I: pilocyticI: pilocytic II: fibrillary, gemistocyticII: fibrillary, gemistocytic III: anaplasticIII: anaplastic IV: glioblastoma (var. gliosarcoma, GC GBM)IV: glioblastoma (var. gliosarcoma, GC GBM) Oligodendroglial:Oligodendroglial: II: oligodendroglioma, III: anaplasticII: oligodendroglioma, III: anaplastic Ependymal:Ependymal: I: subependymoma, II: ependymoma, III: anaplasticI: subependymoma, II: ependymoma, III: anaplastic
    • 3. Classification of CNS tumorsClassification of CNS tumors Neuronal tumors:Neuronal tumors: Gangliocytoma, ganglioglioma, esthesioneuroblastomaGangliocytoma, ganglioglioma, esthesioneuroblastoma Neuroblastic/glioblastic origin:Neuroblastic/glioblastic origin: Neuroblastoma, medulloblastoma (PNET), RBNeuroblastoma, medulloblastoma (PNET), RB Pineal parenchymal origin:Pineal parenchymal origin: Pineocytoma, pineoblastomaPineocytoma, pineoblastoma Meningeal origin:Meningeal origin: Meningioma, atypical meningioma, malignant meningiomaMeningioma, atypical meningioma, malignant meningioma Germ cell origin:Germ cell origin: Pure germinoma, dysgerminomaPure germinoma, dysgerminoma MPNSTMPNST ChordomaChordoma
    • 4. High cellularity/Nuclear atypiaHigh cellularity/Nuclear atypia Geographic necrosis/Geographic necrosis/ PseudopalisadingPseudopalisading Vascular proliferationVascular proliferation WHO Grading SystemWHO Grading System
    • 5. WHO Grading SystemWHO Grading System # of# of morphologicmorphologic criteriacriteria MedianMedian survivalsurvival (yrs)(yrs) WHO Gr IWHO Gr I 00 >10>10 WHO Gr IIWHO Gr II 11 77 WHO Gr IIIWHO Gr III 22 33 WHO Gr IVWHO Gr IV 3-43-4 1-21-2
    • 6. Molecular ProgressionMolecular Progression
    • 7. Predisposing FactorsPredisposing Factors  Cranial irradiationCranial irradiation  NCI Case-control Study:NCI Case-control Study:  GST polymorphismsGST polymorphisms  Cyt P450 isoenzymesCyt P450 isoenzymes  Inverse relationship to allergic and AI dzInverse relationship to allergic and AI dz  No relationship to cell phones orNo relationship to cell phones or transmission lines*transmission lines*
    • 8. Diagnosis: MRI in HGGDiagnosis: MRI in HGG T1 weighted post-gadolinium T2 weighted image
    • 9. High grade gliomas: SurgeryHigh grade gliomas: Surgery Maximal surgical resection (GTR vs NTR)Maximal surgical resection (GTR vs NTR) • rapid symptom resolution, decreased mass effectrapid symptom resolution, decreased mass effect • adequate tissue for accurate histologic grading,adequate tissue for accurate histologic grading, • reduces tumor burden prior to chemoradiationreduces tumor burden prior to chemoradiation  Reoperation for recurrent diseaseReoperation for recurrent disease • MS with reoperation for recurrent GBM: 14-36MS with reoperation for recurrent GBM: 14-36 weeksweeks • MS with reoperation for recurrent AA: 56-88MS with reoperation for recurrent AA: 56-88 weeksweeks Harsh GR et al. Neurosurgery 1987Harsh GR et al. Neurosurgery 1987
    • 10. HGG: RadiationHGG: Radiation  Brain Tumor Study Group: AdditionBrain Tumor Study Group: Addition of adjuvant WBRT increased MSof adjuvant WBRT increased MS from 14 to 36 weeks*from 14 to 36 weeks*  Shift from WBRT toShift from WBRT to focal EBRTfocal EBRT****  Dose-response relationship***Dose-response relationship*** *Walker MD et al. J Neurosurg 1978*Walker MD et al. J Neurosurg 1978 **Liang BC, et al. J Neurosurg 1991**Liang BC, et al. J Neurosurg 1991 ***Walker MD, Int J Radiat Oncol Biol Phys 1979***Walker MD, Int J Radiat Oncol Biol Phys 1979
    • 11. HGG: RadiationHGG: Radiation  Phase II studies of high-dose boostPhase II studies of high-dose boost added to standard XRT: OS benefitadded to standard XRT: OS benefit  Randomized Phase III trial of SRSRandomized Phase III trial of SRS boost: No added benefitboost: No added benefit
    • 12. HGG: Single Agent ChemoHGG: Single Agent Chemo 1978:1978: BTSG (Protocol 69-01):BTSG (Protocol 69-01): Walker, MD. J Neurosurg 1978Walker, MD. J Neurosurg 1978 18-month survival:18-month survival: WBRT + carmustine (19%) > WBRT (4%)WBRT + carmustine (19%) > WBRT (4%) 1983: BTSG (Protocol 75-01):1983: BTSG (Protocol 75-01): Green, SB. Cancer Treat Rep 1983Green, SB. Cancer Treat Rep 1983 WBRT + procarbazine = WBRT + carmustineWBRT + procarbazine = WBRT + carmustine
    • 13. HGG: Combination chemoHGG: Combination chemo Northern California Oncology Group protocol 6G61Northern California Oncology Group protocol 6G61 Randomized trial comparing PCV to BCNU after adjuvant radiotherapyRandomized trial comparing PCV to BCNU after adjuvant radiotherapy PCV improves TTP and OS in Anaplastic AstrocytomaPCV improves TTP and OS in Anaplastic Astrocytoma Levin VA, Int J Radiation Oncology Biol. Phys. 1990Levin VA, Int J Radiation Oncology Biol. Phys. 1990 TreatmentTreatment AA (50AA (50thth )) GBM (50GBM (50thth )) TTP: BCNUTTP: BCNU 62.7 weeks62.7 weeks 34.4 weeks34.4 weeks TTP: PCVTTP: PCV 125.6 weeks125.6 weeks 37.4 weeks37.4 weeks Survival: BCNUSurvival: BCNU 82.1 weeks82.1 weeks 57.4 weeks57.4 weeks Survival: PCVSurvival: PCV 157.1 weeks157.1 weeks 50.4 weeks50.4 weeks
    • 14. Adjuvant Chemo: CombinationAdjuvant Chemo: Combination Fine et al. Cancer, 1993:Fine et al. Cancer, 1993: Meta-analysis of 16 randomized trials, 17-year period, 3000Meta-analysis of 16 randomized trials, 17-year period, 3000 patients (GBM and AA), assigned to WBRTpatients (GBM and AA), assigned to WBRT ++ nitrosoureasnitrosoureas • Absolute increase in survival with addition of chemo was 10.1% at 1Absolute increase in survival with addition of chemo was 10.1% at 1 year, 8.6% at 2 yearsyear, 8.6% at 2 years • Median survival increased from 9.4 to 12 monthsMedian survival increased from 9.4 to 12 months Medical Research CouncilMedical Research Council.. JCO, 2001:JCO, 2001: Randomized study where 674 patients (GBM and AA) were treatedRandomized study where 674 patients (GBM and AA) were treated with surgery + RTwith surgery + RT ++ PCVPCV • MS of GBM: 9.5 monthsMS of GBM: 9.5 months vv 10 months; MS of AA: 13 months10 months; MS of AA: 13 months Stewart, LA. Lancet, 2002:Stewart, LA. Lancet, 2002: Meta-analysis of 12 RCTs, 3004 patients, compared RT alone to RTMeta-analysis of 12 RCTs, 3004 patients, compared RT alone to RT + chemo+ chemo • Absolute increase in survival with addition of chemo was 6% at 1Absolute increase in survival with addition of chemo was 6% at 1 yearyear • Median survival increased by 2 monthsMedian survival increased by 2 months
    • 15. Newer agentsNewer agents Temozolomide:Temozolomide:  Novel alklyating agentNovel alklyating agent  Orally active, 100%Orally active, 100% bioavailablebioavailable  Pro drug with good CSFPro drug with good CSF penetration – convertedpenetration – converted to an active metaboliteto an active metabolite (MTIC) in CNS(MTIC) in CNS  Well tolerated/immuneWell tolerated/immune suppressionsuppression  MGMT silencing –MGMT silencing – molecular markermolecular marker N H N O N N H H2N
    • 16. HRQOL: TMZ vs PCB for recurrent GBM:HRQOL: TMZ vs PCB for recurrent GBM: Osoba et al. JCO 2000Osoba et al. JCO 2000
    • 17. TMZ in Newly Diagnosed GBM:TMZ in Newly Diagnosed GBM: Stupp NEJM 2005Stupp NEJM 2005
    • 18. Stupp NEJM 2005Stupp NEJM 2005 PFS Benefit OS Benefit
    • 19. MGMT gene methylationMGMT gene methylation Hegi ME et al. NEJM 2005Hegi ME et al. NEJM 2005
    • 20. Glioblastoma ResearchGlioblastoma Research
    • 21. Overcoming ResistanceOvercoming Resistance
    • 22. Individualized therapyIndividualized therapy
    • 23. Targeting angiogenesisTargeting angiogenesis  BevacizumabBevacizumab  AZD2171AZD2171  Vatalanib (PTK 787)Vatalanib (PTK 787)  Vandetanib (ZD6474)Vandetanib (ZD6474)
    • 24. Bevacizumab/IrinotecanBevacizumab/Irinotecan  Phase II study (Phase II study (Vredenburgh et al, JCO 2007Vredenburgh et al, JCO 2007):):  63% radiographic response rates in63% radiographic response rates in AA+GBM study (CCR, Feb 2007)AA+GBM study (CCR, Feb 2007)  6-month PFS 46%, 6-month OS 77% in6-month PFS 46%, 6-month OS 77% in GBMGBM (n=35; 1 CNS bleed, 4 DVT/PE;(n=35; 1 CNS bleed, 4 DVT/PE; JCO, Oct 2007JCO, Oct 2007))
    • 25. AZD2171 (Cediranib)AZD2171 (Cediranib)  Phase II multicenter trialPhase II multicenter trial  56% radiographic partial responses56% radiographic partial responses  25% APFS25% APFS  PFS 117 daysPFS 117 days  OS 221 daysOS 221 days  Phase III RCT lomustine, vs AZD2171Phase III RCT lomustine, vs AZD2171 vs combinationvs combination
    • 26. Novel agentsNovel agents  EGFR inhibitors (erlotinib)EGFR inhibitors (erlotinib)  PKC inhibitors (enzastaurin)PKC inhibitors (enzastaurin)  Integrin inhibitors (cilengitide)Integrin inhibitors (cilengitide)  mTOR inhibitors (everolimus, temsirolimus)mTOR inhibitors (everolimus, temsirolimus)
    • 27. Metastatic Brain DiseaseMetastatic Brain Disease  150,000 annual cases in the US150,000 annual cases in the US  10-20% of all cancers will metastasize10-20% of all cancers will metastasize  Most common to brain:Most common to brain:  Lung cancerLung cancer  BreastBreast  MelanomaMelanoma  KidneyKidney
    • 28. Metastatic Brain DiseaseMetastatic Brain Disease Standard therapy:Standard therapy:  Whole brain radiationWhole brain radiation  Stereotactic radiosurgeryStereotactic radiosurgery  Surgical resectionSurgical resection  Combination of the aboveCombination of the above NO SYSTEMIC THERAPIESNO SYSTEMIC THERAPIES The Basic premise: BBB is intactThe Basic premise: BBB is intact
    • 29. The Blood-Brain BarrierThe Blood-Brain Barrier
    • 30. BBB: Drug transportersBBB: Drug transporters
    • 31. CNS Metastases: Novel ApproachesCNS Metastases: Novel Approaches  NanoparticlesNanoparticles  ImmunoliposomesImmunoliposomes  Peptide vectorsPeptide vectors  Endogenous-carrier mediatedEndogenous-carrier mediated transporttransport  Small molecule TKIsSmall molecule TKIs

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