Neuro-Oncology - Brown

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  • We have incorporated early assessment of activity by PET neuroimaging into XXXX, a Phase I study for patients with newly diagnosed GBM. Following standard RT and TMZ, we will determine the MTD of everolimus in an adjuvant combination with TMZ. FDG PET will be performed before and after everolimus administration. A Phase II study to evaluate efficacy will follow this study.
  • We have incorporated early assessment of activity by PET neuroimaging into XXXX, a Phase I study for patients with newly diagnosed GBM. Following standard RT and TMZ, we will determine the MTD of everolimus in an adjuvant combination with TMZ. FDG PET will be performed before and after everolimus administration. A Phase II study to evaluate efficacy will follow this study.
  • Following this theme, NCCTG recently received CTEP approval to lead N0577, a new international Phase III Intergroup trial for1p/19q codeleted newly diagnosed anaplastic oligo patients. This study will be performed with RTOG, ECOG, NCIC, EORTC and NCI, and addresses two potentially practice-changing question. First, whether there is a survival advantage of combined TMZ and RT over RT alone or TMZ alone, and second, whether RT can be delayed with TMZ alone. Numerous translational and QOL correlates accompany this study.
  • currently, we have over 60 patients registered, and 31 randomized.
    current experience confirms our concern that interobserver variation
    between pathologists is an issue as of 9/08
  • Revised 11-8-07 mls
  • As of 3/1 enrolled 37 pts over 15 months.
  • Neuro-Oncology - Brown

    1. 1. 77thth Annual NCCTGAnnual NCCTG Patient Advocate SymposiumPatient Advocate Symposium Neuro-OncologyNeuro-Oncology Paul Brown, MDPaul Brown, MD Professor of OncologyProfessor of Oncology Department of Radiation OncologyDepartment of Radiation Oncology Mayo ClinicMayo Clinic Rochester, MNRochester, MN
    2. 2. Brain Cancers: FrequencyBrain Cancers: Frequency • Total new primaryTotal new primary 17,500 (1.35%)17,500 (1.35%) • Total deaths primaryTotal deaths primary 14,000 (2.35%)14,000 (2.35%) • Total metastatic tumorsTotal metastatic tumors 300,000300,000 – ~30% of patients with cancer develop brain~30% of patients with cancer develop brain metastases eventuallymetastases eventually
    3. 3. Types of Primary Adult Brain TumorsTypes of Primary Adult Brain Tumors GliomasGliomas • Low GradeLow Grade – PilocyticPilocytic – OligodendrogliomaOligodendroglioma – Mixed tumorsMixed tumors – AstrocytomasAstrocytomas • High GradeHigh Grade – AnaplasticAnaplastic – Glioblastoma MultiformeGlioblastoma Multiforme OtherOther • Primary CNSPrimary CNS lymphomaslymphomas • Germ cell tumorsGerm cell tumors • EpendymomasEpendymomas • MedulloblastomaMedulloblastoma • Pituitary adenomasPituitary adenomas • MeningiomasMeningiomas • ChordomasChordomas WorseSurvivalWorseSurvival NCCTGNCCTG ResearchResearch
    4. 4. Glioblastoma MultiformeGlioblastoma Multiforme • Rapid progressionRapid progression • Greater extent resectionGreater extent resection beneficialbeneficial •Radiation doubles survivalRadiation doubles survival T1 post-contrastT1 post-contrast FLAIRFLAIR
    5. 5. High Grade GliomaHigh Grade Glioma BackgroundBackground Time periodTime period 1 Yr Surv1 Yr Surv 5 Yr Surv5 Yr Surv McGill UnivMcGill Univ 1939-19581939-1958 44%44% 7%7% Mayo ClinicMayo Clinic 1990-19941990-1994 47%47% 10%*10%* Jean Bouchard (McGill Univ. Montreal), Radiation therapy of tumors and diseases of the nervous system, Lea &Jean Bouchard (McGill Univ. Montreal), Radiation therapy of tumors and diseases of the nervous system, Lea & Febinger 1966.Febinger 1966. Buckner et al. "A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in theBuckner et al. "A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma."treatment of patients with newly diagnosed high-grade glioma." CancerCancer 9292(2): 420-33, 2001.(2): 420-33, 2001. *Values taken from curves*Values taken from curves Very Frustrating!!!
    6. 6. Focal RT daily Temozolomide Concomitant TMZ/RT* Adjuvant TMZ Weeks6 10 14 18 22 26 30 RT Alone R 0 573 patients accrued.573 patients accrued. Phase III Study: New GBMPhase III Study: New GBM Radiation +/- TemozolomideRadiation +/- Temozolomide
    7. 7. EORTC/NCIC Phase III GBM Trial:EORTC/NCIC Phase III GBM Trial: Overall SurvivalOverall Survival months 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 P<0.0001 TMZ/RT RT %
    8. 8. OS no different thanOS no different than EORTC RT + TMZEORTC RT + TMZ
    9. 9. CM923704-9 N057K:N057K: Phase I Newly Dx GBM:Phase I Newly Dx GBM: RT+TMZ+ RAD001: Dr. SarkariaRT+TMZ+ RAD001: Dr. Sarkaria RT (60 Gy) + TMZ 75 mg/M2/d + RAD-001 q wk Newly Dx GBM TMZ 200 mg/M2 D1-5 q 28d + RAD001- 1,8,15,21 q 28d Translational correlates (Phase I) • Pre and post RAD001 FDG-PET • Phase I limited JAX and RST Open Sample Size: Phase I 9-30 Phase II: 120
    10. 10. CM923704-10 N0874:N0874: Phase II Newly Dx GBM:Phase II Newly Dx GBM: RT+TMZ + Vorinostat (SAHA) Dr. Galanis/WenRT+TMZ + Vorinostat (SAHA) Dr. Galanis/Wen RT (60 Gy) +RT (60 Gy) + TMZTMZ 75 mg/M2/d +75 mg/M2/d + SAHA q400mgSAHA q400mg 5d/7d5d/7d Newly DxNewly Dx GBMGBM SAHA500mg D1-7,SAHA500mg D1-7, 15-21 q 28d +15-21 q 28d + TMZ 150 mg/M2 DTMZ 150 mg/M2 D 1-5 q 28 D**1-5 q 28 D** Activated to GroupActivated to GroupNCCTG/ABTCNCCTG/ABTC IntergroupIntergroup Sample Size: Phase I: 12-24 Phase II: 108 Translational correlates • Neurocognitive testing • Tumor H1-4 acetylation, MGMT, pAKT, cdK inhibitors (p21Waf-1/Cyp1 , p27Kip-1 )
    11. 11. CM923704-11 N0877:N0877: Phase I-II Randomized Newly Dx GBM:Phase I-II Randomized Newly Dx GBM: RT+TMZ +Dasatanib vs Placebo: Dr. LaackRT+TMZ +Dasatanib vs Placebo: Dr. Laack RT (60 Gy) + TMZ 75mg M2/D+ placebo Newly Dx GBM TMZ 150-200 mg/M2 D1-5, q 28d + Placebo D1-5 X 6 cycles Upcoming RT (60 Gy) + TMZ 75mg/M2/D + Dasatanib 40- 100mg* bid TMZ 150-200 mg/M2 D1-5, q 28d + Dasatanib D1-5 or placebo X 6 cycles Translational: 1)QOL; 2) Tumor Tissue: receptors, signaling and gene expression 1:2 Random Arm A Arm B N=146
    12. 12. CM923704-12 Randomized Phase II Recurrent GBMRandomized Phase II Recurrent GBM ComparisonsComparisons Yung WKA, et al. Br J Cancer. 2000;83:588-593. Goli, et al. abstract #2003, Clinical Science Symposium ASCO 2007. Cloughesy, et al. abstract #2010, oral presentation ASCO 2008. TMZTMZ BV-Phase IIRBV-Phase IIR BV-DukeBV-Duke 6 mo PFS6 mo PFS 21%21% 50%50% 43%43% Median OSMedian OS 7.3 mos7.3 mos 8.9 mos8.9 mos 9.2 mos9.2 mos
    13. 13. CM923704-13 GBMGBM TissueTissue availableavailable 30 Gy +30 Gy + TMZTMZ R#R# AA NN DD OO MM II ZZ EE 30 Gy +30 Gy + TMZ +TMZ + BevBev 30 Gy +30 Gy + TMZ + PlaceboTMZ + Placebo TMZ d 1-5 of 28-dTMZ d 1-5 of 28-d cycle + Placebocycle + Placebo 12 cycle max12 cycle max ## Stratify by: (Random 10d post start RT)Stratify by: (Random 10d post start RT) Recursive partitioning analysis (RPA) class (III vs IV vs V)Recursive partitioning analysis (RPA) class (III vs IV vs V) MGMT methylation statusMGMT methylation status Molecular profileMolecular profile TMZ d 1-5 of 28-dTMZ d 1-5 of 28-d cycle + Bevcycle + Bev 12 cycle12 cycle maxmax Sample Size= 720 Primary endpoints: OS and PFS *Analysis for MGMT*Analysis for MGMT methylation, molec profilemethylation, molec profile R0825:R0825: Phase III Randomized Newly Dx GBM:Phase III Randomized Newly Dx GBM: RT+TMZ +/- Bevacizumab: Brown/JaeckleRT+TMZ +/- Bevacizumab: Brown/Jaeckle Upcoming
    14. 14. OligodendrogliomaOligodendroglioma • Classified as low-grade orClassified as low-grade or anaplasticanaplastic • Very responsive toVery responsive to treatment: chemotherapytreatment: chemotherapy and radiationand radiation • Prognosis and treatmentPrognosis and treatment response stronglyresponse strongly correlated with 1p & 19qcorrelated with 1p & 19q LOHLOH 100% response to chemotherapy with 1p 19q LOH
    15. 15. Intergroup-9402Intergroup-9402 Oligo,Oligo, MixedMixed n= 289n= 289 RR AA NN DD OO MM II ZZ EE PCV 4 cyclesPCV 4 cycles →→ RTRT RTRT
    16. 16. Copyright © American Society of Clinical Oncology Cairncross, G. et al. J Clin Oncol; 24:2707-2714 2006 Kaplan-Meier estimates of overall survival by treatment group
    17. 17. Copyright © American Society of Clinical Oncology Cairncross, G. et al. J Clin Oncol; 24:2707-2714 2006 Kaplan-Meier estimates of overall survival by 1p and 19q deletion Median survival 1p,19q intact equal to Gr3 astroMedian survival 1p,19q intact equal to Gr3 astro
    18. 18. CM923704-18 NewlyNewly DiagnosedDiagnosed AO / AOA:AO / AOA: AssessAssess 1p/19q1p/19q No (orNo (or single)single) 1p/19q1p/19q deletiondeletion CODELCODEL NCCTGNCCTG N0577N0577 1p/19q1p/19q deletiondeletion CATNONCATNON EORTC 26503EORTC 26503 PROPOSED NEWLY DIAGNOSEDPROPOSED NEWLY DIAGNOSED ANAPLASTIC GLIOMAANAPLASTIC GLIOMA INTERGROUP TRIALSINTERGROUP TRIALS
    19. 19. CM923704-19 NCCTG N0577:NCCTG N0577: Intergroup Phase III AnaplasticIntergroup Phase III Anaplastic Oligo / Mixed Glioma 1p/19q CodeletedOligo / Mixed Glioma 1p/19q Codeleted Translational correlates • 1p/19q translocation • MGMT promotor methylation • QOL/neurocog Newly Diagnosed AO/AO 1p/19q co-deletion RT (5960cGy) TMZ x 12 cycles RT + TMZ → TMZ (Stupp) RT vs. RT +TMZ: Primary endpoint - OS N=245 N=245 N=50
    20. 20. CM923704-20 EORTC 26053 CATNON: Gr 3 AG, 0-1 deletionsEORTC 26053 CATNON: Gr 3 AG, 0-1 deletions Ph III RT+/-TMZPh III RT+/-TMZ →→ TMZ vs ObservationTMZ vs Observation • Pre-study 1p/19q testing • Stratification: - Methylation status • Primary endpoint: OS • Secondary endpoints: • PFS • Quality of life • Cognition • Neurological deterioration free survival No adjuvant treatment follow- up Adjuvant TMZ 200 mg D1- 5 q28D, X 12 mo R A N D O M I Z A T I O N S U R G E R Y RT 59.4 Gy + concurrent temozolomide 75mg/m2/D RT 59.4 Gy Activated in Europe, Pending in US N=680
    21. 21. Low-Grade GliomasLow-Grade Gliomas
    22. 22. Low Grade AstrocytomasLow Grade Astrocytomas TypesTypes • Pilocytic astrocytomaPilocytic astrocytoma • OligodendrogliomaOligodendroglioma • OligoastrocytomaOligoastrocytoma • Low gradeLow grade astroctyomaastroctyoma • Occur in youngerOccur in younger patients (20-50 years)patients (20-50 years) • Diffuse in natureDiffuse in nature • Slow growingSlow growing • More likely to presentMore likely to present with seizurewith seizure • Responsive to radiationResponsive to radiation
    23. 23. Survival 0.0 0.2 0.4 0.6 0.8 1.0 0 10 20 30 Survival Time (yrs) GTR STR GTR STR CP1288306-14 P<0.0001 P=0.004 OS PFS •314 pts (1960-1992)314 pts (1960-1992) •75% adjuvant Tx75% adjuvant Tx •Median F/U 14 yrsMedian F/U 14 yrs •GTR better OS andGTR better OS and PFSPFS •Multivariate AnalysesMultivariate Analyses -Benefit for adjuvant RT-Benefit for adjuvant RT Schomas SNO 2007Schomas SNO 2007 Mayo Clinic Experience-Long TermMayo Clinic Experience-Long Term
    24. 24. CM923704-24 Focal RT daily — 28 x 180 cGy Total dose 50.4 Gy Temozolomide 75 mg/m2 po qd for 6 weeks, then 150-200 mg/m2 po qd day 1-5 q 28 days for 12 cycles Concomitant TMZ/RT Adjuvant TMZ Weeks6 10 14 18 22 26 30 RT Alone R 0 *Symptomatic = uncontrolled headaches or seizures, focal deficits, cognitive symptoms E0F05 Phase III Symptomatic* or Progressive LGG: RT +/E0F05 Phase III Symptomatic* or Progressive LGG: RT +/ TemozolomideTemozolomide N= 540 Upcoming
    25. 25. Brain MetastasesBrain Metastases
    26. 26. Management of Brain MetsManagement of Brain Mets Therapeutic ChoicesTherapeutic Choices • WBRT alone • Surgical resection +/- WBRT –Single brain metastasis • Stereotactic radiosurgery* +/- WBRT *high dose radiation to small, discrete, well-defined target with rapid dose fall-off
    27. 27. N0574N0574 1-3 Brain1-3 Brain Mets on MRIMets on MRI QOL,QOL, NeurocogNeurocog RadiosurgeryRadiosurgery Radiosurgery +Radiosurgery + WBRTWBRT

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