CNS Updated December 2015 by Dr. Carrie Yeung (PGY-5 Medical Oncology Resident, University of Toronto)

Transcription

1 CNS Updated December 2015 by Dr. Carrie Yeung (PGY-5 Medical Onclgy Resident, University f Trnt) Reviewed by Dr. Rger Tsang (Staff Medical Onclgist, University f Calgary) and Dr. Warren Masn (Staff Medical Onclgist, University f Trnt) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 1.7% f all cancers in males in Canada; 1.3% in females in Canada - Mst cmmn slid tumr in children - 2 nd leading cause f death frm cancer in children - 3 rd leading cause f cancer-related death fr adlescents and adults age Adults glimas accunt fr 50% and meningima 25-30% f symptmatic primary brain tumrs - Men>Wmen - Gliblastma increases with age dramatically increases after age 45 peak incidence ~ age 64 RISK FACTORS - Inizing radiatin Children treated with radiatin fr ALL, NHL, cranipharyngima - HIV and EBV fr CNS lymphma - Chemicals: pesticides, PVC, frmaldehyde - Neurfibrmatsis Type 1 and 2 - Vn Hippel-Lindau disease - Turct Syndrme Gliblastma (MLH1 and PMS2 genes) Medullblastma (APC gene) - Li-Fraumeni Syndrme Gliblastma Medullblastma - Increased risk f glimas TP53, IDH, PTEN, CDKN2, EGFR - Cell phne use/ radiatin expsure unclear risk factrs B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS Generalized

2 - Headache nausea and vmiting (40%) change in prir headache pattern wrsens with change in bdy psitin that raises intrathracic pressure (cugh, sneeze, Valsalva) wrse at night; may awaken patient - Seizures can be fcal r generalized typically repetitive and steretyped in given patient mre cmmn in lw-grade glimas - Syncpe Secndary t significant rise in ICP cutting ff cerebral perfusin - Cgnitive dysfunctin Memry and md changes Mre cmmn in high-grade glimas Fcal - Weakness tumr-assciated weakness respnsive t high-dse dexamethasne secndary t edema rather than direct tumr invlvement cranitmy may be cnsidered t relieve mass effect and lessen crticsterid requirement even if tumr nt resectable fr curative intent mre cmmn in high-grade glimas - Sensry lss - Aphasia may be cnfused with dementia r psychiatric disrder (depressin r psychsis) subacute psychsis in patient w/ psychiatric histry is diagnsis f exclusin neurimaging t r/ rganic cause - Visual-spatial dysfunctin INVESTIGATIONS Diagnstic Imaging: examine fr papilledema and presence f bitempral hemianpsia (tumr-related cmpressin f ptic chiasm) - MRI with Gadlinium Test f chice Usually nly test needed High-grade glimas Hypintense n T1 and enhance hetergenerusly fllwing cntrast infusin Tumr distinguished frm surrunding hypintense signal f edema n T1 Astrcytmas (regardless f histlgic grade) increased T2 and FLAIR As a rule the amunt f cntrast enhancement increases with higher grades f malignant disease Ring enhancement is characteristic f GBM Pilcytic astrcytma enhances but is lw-grade tumr - Magnetic Resnance Spectrscpy (MRS) Imprve differentiatin f lcally infiltrative brain tumrs frm ther well-circumscribed intracranial lesins Analyzes chemical cmpsitin in an area f interested selected by radilgist N-acetylaspartate signals presence f neurns; decreased in glimas Chline cmpnent f cell membrane; increased in tumrs

3 Lactate anaerbic respiratin; present in tumrs but als infectin r strke 2-hydrxyglutarate increased in IDH1 and IDH2 mutatins Des nt differentiate between types f infiltrative r circumscribed lesins Signals degraded by bne and CSF less useful fr skull base and periventricular lesins - Perfusin MRI Imaging f bld flw in brain tumrs increased perfusin in newly diagnsed r recurrent brain tumrs reflects presence f hypervascularity Dne with either blus f Gad. (dynamic cntrast MRI r dynamic susceptibility cntrast MRI) r with magnetic pulsatin f water mlecules - CT Replaced by MRI as imaging f chice but useful in: Detect bne r vascular invlvement Mets t skull base, clivus r regins near framen magnum Emergency situatins r when MRI cntraindicated - staging prcedures nt necessary as mst primary brain tumrs remain lcalized - MRI f spine and CSF analysis fr: CNS germ cell tumrs Ependymma Primary CNS lymphma Medullblastma Diagnstic Prcedures: - tissue btained by steretactic bipsy r pen surgery - crticsterid use shuld be avided prir t bipsy r surgery if suspect: primary CNS lymphma infectins prcess - Surgery Initial therapy fr all patients Gals btain tissue, reduce mass effect, reduce tumr cell burden Maximal safe resectin if feasible If nt aim fr subttal resectin r pen bipsy r steretactic bipsy Primary CNS lymphma r CNS germ cell tumrs bipsy nly since primary therapy is chemtherapy and/r radiatin - CSF analysis fr: CNS germ cell tumrs Ependymma Primary CNS lymphma Medullblastma PATHOLOGY & MOLECULAR BIOLOGY Relevant Mlecular Bilgy C-deletin f 1p/19q - Mst imprtant prgnstic and predictive factr fr imprved survival in ligdendrglial tumrs due t mre indlent natural histry and better respnse t therapy

4 IDH1 Mutatin - Iscitrate dehydrgenase 1 (IDH1) and IDH2 mutatins prgnstic factr assciated with imprved survival in all glimas independent f treatment - Can be fund in tumrs with r withut 1p/19q c-deletin Methylguanine Methyltransferase (MGMT) Prmter Methylatin - MGMT enzyme respnsible fr DNA repair fllwing chemtherapy - MGMT silenced by methylatin f its prmter Absence f methylatin pr prgnsis; decreased benefit frm temzlmide Presence f methylatin superir survival regardless f treatment received; als predictive f respnse t TMZ in newly diagnsed GBM Present in abut 50% f GBM patients >70 years f age (mst imprtant mlecular prgnstic marker in elderly GBM ppulatin) Chrmsme 10q lss - Pr prgnstic and predictive factr in ligdendrglial tumrs - Mre cmmn in GBM Cmmn Histlgy Glimas - general term fr tumrs arising frm glial cells Astrcytma start in glial cells called astrcytes Oligdendrglimas start in glial cells called ligdendrcytes Ependymmas start in glial cells called ependymal cells (lines ventricles) - 30% f brain tumrs are glimas - usually fast-grwing Mixed Glimas - mre than ne type f cell - ligastrcytma cells f bth ligdendrglimas and astrcytmas - treatment based n fastest grwing cmpnent f tumr - increasingly based n mlecular prfile f tumr Meningimas - arises in meninges that line uter part f brain and spinal crd - mst cmmn brain tumr in adults (nt actually brain tumrs) WHO Grading System f CNS Tumrs - Based n 4 histlgical features Increased cellularity Mitses Endthelial prliferatin necrsis - Grade 1: benign (ex. pilcytic astrcytma)

5 - Grade 2: Diffuse infiltrating lw-grade tumrs w/ nly increased cellularity - Grade 3: Anaplastic w/ mitses - Grade 4: Gliblastma multifrme w/ endthelial prliferatin and/r tumr necrsis Lw-Grade Infiltrative Astrcytmas and Oligdendrglimas - WHO grade 2 - Cmmn tumr types: Diffuse astrcytma Oligdendrglima characteristic chrmsmal abnrmalities: IDH gene mutatin 1p/19q c-deletin (50%) pathgnmnic diagnstic feature majrity als have IDH1 deletin Gd prgnstic feature superir survival regardless f treatment >90% chemsensitivity with lng duratin f respnse Mixed ligastrcytmas - Pr prgnstic factrs: Age >=40 KPS <70 Largest dimensin tumr >=6cm Tumr crssing midline Neurlgical deficit befre resectin - High risk if >=3 f abve pr prgnstic features - 5 year survival rate: ligdendrglima 70% mixed glimas 56% astrcytma 37% Anaplastic Glimas - WHO Grade 3 - Anaplastic astrcytma 6% f all glimas IDH1 and IDH2 mutatins favrable prgnsis Median survival 65 mnths (mutatin psitive) vs. 20 mnths (wild-type IDH1 r IDH2) - Anaplastic ligdendrglima rare 50% lss f heterzygsity f chrmsmes 1p and 19q pathgnmnic diagnstic feature superir survival regardless f treatment increased sensitivity t chemtherapy 50% patients alive at 5 years GBM - WHO Grade 4-54% f all glimas - mst lethal 1 year survival 33% 5 year survival <5%

6 - nearly all recur - prgnstic factrs: age PPS Lack f necrsis Extent f resectin IDH1 MGMT - IDH1 and IDH2 mutatins favrable prgnsis Median survival 31 mnths (mutatin psitive) vs. 15 mnths (wild-type IDH1 r IDH2) Less cmmn in elderly patients - Methylguanine methyltransferase (MGMT) prmter methylatin Absence f methylatin pr prgnsis; decreased benefit frm temzlmide Presence f methylatin superir survival regardless f treatment received prevents transcriptin f MGMT gene and expressin f MGMT MGMT nrmally reverses effects f methylating agents like temzlmide Present in abut 50% f GBM patients >70 years f age (mst imprtant mlecular prgnstic marker in elderly GBM ppulatin) - DNA methylatin (CpG Island Methylatr Phentype = CIMP) Favrable prgnsis MGMT methylatin assciated with CIMP - Subtypes prneural (better prgnsis), classical, prliferative, mesenchymal C) TREATMENT LOW GRADE ASTROCYTOMAS AND OLIGODENDROGLIOMAS Primary and Adjuvant Treatment - Maximal surgical resectin if pssible - 1p/19q testing if ligdendrglima - IDH1 and IDH2 rutine mutatin testing has becme standard in sme centres (althugh nt currently recmmended by NCCN as impact n treatment unclear) - Lw risk patients If grss ttal resectin achieved may be bserved w/ adjuvant treatment 50% will prgress eventually - High risk patients Adjuvant chemtherapy with PCV and radiatin RTOG 9802 Phase III Randmized trial - If nly had steretactic bipsy, pen bipsy r subttal resectin: Immediate fractinated EBRT r chemtherapy If gd prgnstic factrs, chem and RT can be deferred - Fllw-up: MRI q3-6 mnths x 5years then annually Recurrence - Surgery if resectable fllwed by chemtherapy if patients previusly had fractinated EBRT if n prir radiatin pst-perative chemtherapy r radiatin retreatment with radiatin difficult due t increased risk f neurtxicity and radiatininduced necrsis - if prgressed fllwing chemtherapy ptins are: anther chemtherapy regimen (Temzlmide)

7 Quinn Ja et al. Phase II trial f temzlmide in patients with prgressive lwgrade glima. J Clin Oncl. 2003;21(4): patients treated with temzlide 200mg/m2 ral daily x 5 days q28 day cycle bjective respnse rate 61% (24% CR; 37% PR; 35% stable disease) median PFS 22 mnths 6 mnth PFS 98%; 12 mnth PFS 76% Grade 3 neutrpenia and thrmbcytpenia 1 patient with grade 4 txicity (intracerebral hemrrhage death) Pace A et al. Temzlmide chemtherapy fr prgressive lw-grade glima: clinical benefits and radilgical respnse. Ann Oncl. 2003;14(12):1722 Phase II trial 43 patients treated with temzlmide Respnse Rate 47% (CR 4 patients, 16 PR, 17 stable disease) Median duratin f respnse 10 mnths 6 mnth PFS 76%; 12 mnth PFS 39% re-irradiatin prgressin-free >2 years frm prir radiatin new lesin utside f previus radiatin field recurrence small palliatin Radiatin Therapy Onclgy Grup (RTOG) trial 9802, Phase III study f radiatin therapy with r withut prcarbazine, CCNU, and vincristine (PCV) in lw grade glima Buckner JCet al. J Clin Oncl 32:5s, 2014 (suppl; abstr 2000) Regimen RT alne (54Gy/30#) r RT fllwed by PCV x 6 cycles Primary Endpint OS Inclusin/Exclusin Criteria Grade II astrcytma, ligastrcytma r ligdendrglima age >=40 age<40 and subttal resectin r bipsy Size (N) 251 with median f/u 11.9 years Results Median Survival: 13.3 years (RT+PCV) vs. 7.8 years (RT alne) HR 0.59 Astrcytma fr ligastrcytma (with astrcytma being dminant histlgy) wrse prgnstic factr fr OS cmpared t ligdendrglima r ligastrcytma (with ligdendrglima being dminant histlgy) Txicity (e.g. cmmn txicities verall, cmmn grade 3/4 txicities) Cnclusin grade 2 glima patients with less than grss ttal tumr resectin r >40 years f age, PCV + RT prlngs bth OS and PFS cmpared with RT alne Other Cmments ip/19q deletin and IDH mutatin analyzes nt cmpleted subset f patients that can safely be treated with chemtherapy alne? ANAPLASTIC OLIGODENDROGLIOMA OR OLIGOASTROCYTOMA - maximal surgical resectin if pssible - 1p/19q c-deletin present fractinated EBRT + PCV; NCCN recmmends adjuvant PCV after radiatin (EORTC 26951) ver intensive neadjuvant PCV (RTOG 9402) due t better tlerance radiatin + cncurrent temzlmide als an ptin - 1p/19q c-deletin absent fractinated EBRT standard (NCCN)

8 ? Rle fr adjuvant TMZ (CATNON study t be presented as ASCO 2016) radiatin + cncurrent temzlmide als an ptin KPS <60: Hypfractinated radiatin alne PCV r temzlmide alne Adjuvant Prcarbazine, Lmustine, and Vincristine Chemtherapy in Newly Diagnsed Anaplastic Oligdendrglima: Lng-Term Fllw-Up f EORTC Brain Tumr Grup Study Van den Bent MJ al. J Clin Oncl (3): Regimen 59.4 Gy f RT r the same RT fllwed by six cycles f adjuvant PCV. Primary Endpint OS and PFS Size (N) 368 Results OS: 42.3 mnths (RT+PCV) vs mnths (RT alne) HR 0.75 PFS: 24.3 mnths (RT+PCV) v mnths (RT alne) HR patients 1p/19q cdeletin OS nt reached in RT+PCV vs. 112 mnths in RT grup PFS 157 mnths in RT+PCV vs. 50 mnths RT grup Absent 1p/19q cdeletin OS 25 mnths RT+PCV vs. 21 mnths in RT PFS 15 mnths RT+PCV vs. 9 mnths RT Txicity Cnclusin additin f six cycles f PCV after 59.4 Gy f RT increases bth OS and PFS in anaplastic ligdendrglial tumrs. 1p/19q-cdeleted tumrs derive mre benefit frm adjuvant PCV cmpared with nn- 1p/19q-deleted tumrs. Phase III trial f chemraditherapy fr anaplastic ligdendrglima: lng-term results f RTOG Cairncrss G al. J Clin Oncl (3): Regimen prcarbazine, lmustine, and vincristine (PCV) plus raditherapy (RT) versus RT alne. Primary Endpint OS Size (N) 291 Results OS n difference: 4.6 years RT+PCV vs. 4.7 years RT 1p/19q cdeletin present vs. 1p/19q cdeletin absent Survival RT+PCV 14.7 years vs. 2.6 years 1p/19q cdeletin present median survival: 14.7 years RT+PCV vs. 7.3 years RT 1p/10q cdeletin absent median survival: 2.6 years RT+PCV vs. 2.7 years RT n difference Cnclusin Fr the subset f patients with 1p/19q cdeleted AO/AOA, PCV plus RT may be an especially effective treatment, althugh this bservatin was derived frm an unplanned analysis. Onging Phase III trials: CODEL (revised prtcl: NCIC CTG CEC.6 (ALLIANCE N0577)

9 - 1p/19q deletin patients with anaplastic glimas randmized t either: (includes high risk lw grade glimas) RT fllwed by PCV x6 cycles RT with cncurrent temzlmide fllwed by adjuvant TMZ x6 cycles CATNON - Nn 1p/19q deletin anaplastic glimas randmized t either: RT alne RT with cncurrent temzlmide RT fllwed by temzlmide RT with cncurrent and adjuvant temzlmide ANAPLASTIC ASTROCYTOMA - maximal surgical resectin if pssible - fractinated EBRT standard (NCCN) - radiatin + cncurrent temzlmide als an ptin (extraplatin frm GBM data especially in patients with negative prgnstic factrs lder age, wild type IDH1/2) - KPS <60: Hypfractinated radiatin alne PCV r temlzmide alne NOA-04 randmized phase III trial f sequential radichemtherapy f anaplastic glima with prcarbazine, lmustine, and vincristine r temzlmide Wick WH et al. J Clin Oncl. 2009;27(35):5874 Regimen Arm A: cnventinal raditherapy Arm B1: prcarbazine, lmustine, vincristine (PCV) Arm B2: Temzlmide Primary Endpint Time t treatment failure (TTF) Inclusin/Exclusin Newly diagnsed anaplastic glimas Criteria Size (N) 318 Results Median TTF, PFS and OS similar fr arms A and B1/B2 TTF Arm A 43 mnths; TTF Arm B1/B2 44 mnths N significant difference in TTF between Arm B1 and B2 Extent f resectin imprtant prgnsticatr Anaplastic ligdendrglimas and ligastrcytmas share same and better prgnsis than anaplastic astrcytmas MGMT prmter methylatin, IDH1 mutatin, and ligdendrglial histlgy reduced risk f prgressin MGMT prmter methylatin assciated with prlnged PFS in chemtherapy and raditherapy arm Cnclusin Initial raditherapy r chemtherapy achieved cmparable results in patients with anaplastic glimas. IDH1 mutatins are a nvel psitive prgnstic factr in anaplastic glimas, with a favrable impact strnger than that f 1p/19q cdeletin r MGMT prmter methylatin Onging Phase III trials:

10 - NCT Radiatin Therapy With Cncmitant and Adjuvant Temzlmide r Radiatin Therapy With Adjuvant PCV r Temzlmide Alne in Treating Patients With Anaplastic Glima - NCT Radiatin Therapy With r Withut Temzlmide in Treating Patients With Anaplastic Glima GLIOBLASTOMA - Maximal surgical resectin with preservatin f neurlgic functin cnsidered fr all patients including elderly - Gd PFS and age <70: Adjuvant cncurrent temzlmide and radiatin fllwed by 6 cycles (Stupp R et al.) Additin f bevacizumab did nt imprve survival (Chint OL et al; Gilbert et al.) - Elderly patients unable t have adjuvant cncurrent radiatin and temzlmide (Wick W et al; Malmstrm A et al): Either single agent temzlmide r hypfractinated radiatin alne If MGMT prmter methylatin psitive greatest benefit is frm temzlmide alne ver radiatin N evidence t recmmend either temzlmide alne r raditherapy alne in patients w/ MGMT prmter methylatin - Temzlmide depletes CD4+ T cells in up t 75% f patients risk f PCP. All patients n daily temzlmide during radiatin shuld receive PCP prphylaxis (e.g. Septra) - Fllw-up: Serial MRI 2-6 weeks pst-radiatin then q2-4 mnths x 2-3 years and can increase frequency thereafter MRI can appear wrse during first 3 mnths after cmpletin f radiatin (i.e. pseudprgressin) - Recurrence Distinguish between pseudprgressin and true prgressin (bth may be symptmatic) Surgery (20-30% are candidates fr secnd surgery) Reirradiatin althugh rle uncertain (lack f prspective data) Clinical trial Bevacizumab Friedman HS et al. Bevacizumab Alne and in Cmbinatin With Irintecan in Recurrent Gliblastma. J Clin Oncl 2009; 27(28): Nncmparative phase II trial 167 patients all received prir temzlmide bevacizumab 10 mg/kg alne r in cmbinatin with irintecan 340 mg/m(2) r 125 mg/m(2) (with r withut cncmitant enzyme-inducing antiepileptic drugs, respectively) nce every 2 weeks primary endpints 6 mnth PFS (42.6% Bev alne vs. 50.3% Bev+Irintecan) and bjective respnse rate (28.2% Bev alne; 37.8% Bev+Irintecan) secndary endpints median OS (9.2 mnths Bev alne; 8.7 mnths Bev+ Irintecan) Kresil TN et al. Phase II trial f single-agent bevacizumab fllwed by bevacizumab plus irintecan at tumr prgressin in recurrent gliblastma. J Clin Oncl 2009;27: patients median PFS 16 weeks; 6 mnth PFS 29%; 6 mnth OS 57%; median OS 31 weeks

11 Nitrsureas (PCV, Lmustine [CCNU]) r rechallenge with temzlmide (Perry et al. Phase II trial f cntinuus dse-intense temzlmide in recurrent malignant glima. J Clin Oncl. 2010) e.g. RESCUE prtcl), r etpside - Maintenance Stupp et al. Maintenance Therapy With Tumr-Treating Fields Plus Temzlmide vs Temzlmide Alne fr Gliblastma: Randmized Clinical Trial. JAMA ; 314(23) Interim analysis shwed that adding TTF t maintenance temzlmide significantly imprved PFS and OS - Bttm Line General Apprach: Maximal surgical resectin fllwed by adjuvant cncurrent chemtherapy (with temzlmide) with radiatin, then fllwed by an additinal 6 cycles f temzlmide. - Prgnsis: mnths with treatment; 1/3 surviving t 1 year r <5% 5 year survival withut treatment

12 Raditherapy plus cncmitant and adjuvant temzlmide fr gliblastma. Stupp R et al. N Engl J Med (10): and Effects f raditherapy with cncmitant and adjuvant temzlmide versus raditherapy alne n survival in gliblastma in a randmised phase III study: 5-year analysis f the EORTC-NCIC trial. Stupp R et al. Lancet Oncl 2009;10(5): Regimen Raditherapy alne (fractinated fcal irradiatin in daily fractins f 2 Gy given 5 days per week fr 6 weeks, fr a ttal f 60 Gy) r raditherapy plus cntinuus daily temzlmide (75 mg per square meter f bdy-surface area per day, 7 days per week frm the first t the last day f raditherapy), fllwed by six cycles f adjuvant temzlmide (150 t 200 mg per square meter fr 5 days during each 28-day cycle) Mechanism f ral alkylating agent Actin f Experimental Drug Primary Endpint OS Inclusin/Exclusin Newly diagnsed, histlgically cnfirmed gliblastma Criteria Size (N) 573 patients Results Median survival: 14.6 mnths vs 12.1 mnths (radiatin alne) HR0.63 **MGMT prmter methylatin is an independent favrable prgnstic factr **Patients w/ MGMT prmter methylatin: Median survival: 21.5 mnths (radiatin+temzlmide) vs mnths (radiatin alne) 2 year survival rate: 26.5% vs. 10.4% (radiatin alne) 5 year survival rate: 9.8% vs. 1.9% (radiatin alne) Txicity Grade 3/4 txicity: hematlgic in 7% f patients Cnclusin The additin f temzlmide t raditherapy fr newly diagnsed gliblastma resulted in a clinically meaningful and statistically significant survival benefit with minimal additinal txicity ** Reprted in separate NEJM Paper: Hegi ME et al. MGMT gene silencing and benefit frm temzlmide in gliblastma. N Engl J Med Mar 10;352(10): **

13 Temzlmide versus standard 6-week raditherapy versus hypfractinated raditherapy in patients lder than 60 years with gliblastma: the Nrdic randmised, phase 3 trial Malmstrm A et al. Lancet Oncl (9): Regimen 3 arms temzlmide 200 mg/m(2) n days 1-5 f every 28 days fr up t six cycles hypfractinated raditherapy 34 0 Gy administered in 3 4 Gy fractins ver 2 weeks standard raditherapy 60 0 Gy administered in 2 0 Gy fractins ver 6 weeks Primary Endpint OS Inclusin/Exclusin Criteria newly diagnsed gliblastma age >60 WHO perfrmance scres 0-2 Size (N) 291 patients Results Median verall survival: 8.3 mnths (temzlmide) vs 6 mnths (standard radiatin) N statistically significant difference in median OS between temzlmide (8.3 mnths) and hypfractinated radiatin (7.5 mnths) Patients treated with temzlmide: MGMT prmter methylatin psitive lnger survival rates 9.7 mnths vs. 6.8 mnths (n methylatin) MGMT prmter methylatin status n effect n survival in patients treated with radiatin Patients w/ MGMT prmter methylatin: N difference in OS in patients treated with temzlmide r radiatin Txicity Grade 3/4 txicity: neutrpenia, lymphcytpenia, thrmbcytpenia, raised LFTs, infectins, thrmbemblic events Cnclusin Standard raditherapy was assciated with pr utcmes, especially in patients lder than 70 years. Bth temzlmide and hypfractinated raditherapy shuld be cnsidered as standard treatment ptins in elderly patients with gliblastma. MGMT prmter methylatin status might be a useful predictive marker fr benefit frm temzlmide

14 Temzlmide chemtherapy alne versus raditherapy alne fr malignant astrcytma in the elderly: the NOA-08 randmised, phase 3 trial. Wick W et al. Lancet Oncl (7): Regimen Patients were randmly assigned 100 mg/m(2) temzlmide, given n days 1-7 f 1 week n, 1 week ff cycles, r raditherapy f 60 0 Gy, administered ver 6-7 weeks in 30 fractins f Gy Primary Endpint OS assessed nn-inferirity with a 25% margin, analysed fr all patients wh received at least ne dse f assigned treatment Inclusin/Exclusin Criteria anaplastic astrcytma r gliblastma age > 65 Karnfsky perfrmance scre > 60 Size (N) 412 patients Results Median survival: 8.6 mnths (temzlmide) vs 9.6 mnhts (radiatin) Temzlmide nn-inferir t radiatin MGMT prmter methylatin assciated with lnger OS 11.9 mnths (methylated) vs. 8.2 mnths (unmethylated) Patients w/ MGMT prmter methylatin: Event free survival: 8.4 mnths (temzlmide) vs. 4.6 mnths (radiatin alne) Patients w/ MGMT prmter methylatin: Event free survival: 3.3 mnths (temzlmide) vs. 4.6 mnths (radiatin alne) Txicity Grade 3/4 txicity: neutrpenia, lymphcytpenia, thrmbcytpenia, raised LFTs, infectins, thrmbemblic events Cnclusin Temzlmide alne is nn-inferir t raditherapy alne in the treatment f elderly patients with malignant astrcytma. MGMT prmter methylatin seems t be a useful bimarker fr utcmes by treatment and culd aid decisin-making.

15 Bevacizumab plus raditherapy-temzlmide fr newly diagnsed gliblastma Chint et al. N Engl J Med. 2014;370(8):709. Regimen intravenus bevacizumab (10 mg per kilgram f bdy weight every 2 weeks) r placeb, plus raditherapy (2 Gy 5 days a week; maximum, 60 Gy) and ral temzlmide (75 mg per square meter f bdy-surface area per day) fr 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilgram intravenusly every 2 weeks) r placeb, plus temzlmide (150 t 200 mg per square meter per day fr 5 days), was cntinued fr six 4-week cycles, fllwed by bevacizumab mntherapy (15 mg per kilgram intravenusly every 3 weeks) r placeb until the disease prgressed r unacceptable txic effects develped Primary Endpint OS and PFS Size (N) 458 patients bevacizumab grup; 463 t placeb Results Median survival: n statistical difference Median PFS: 10.6 mnths (Bev) vs. 6.2 mnths (placeb) HR0.64 Crticsterid requirement lwer in Bev. grup QL and PFS maintained lnger in Bev. grup Bev. grup had mre grade 3 adverse events Txicity Grade 3/4 txicity: hematlgic in 7% f patients Cnclusin The additin f bevacizumab t raditherapy-temzlmide did nt imprve survival in patients with gliblastma. Imprved prgressin-free survival and maintenance f baseline quality f life and perfrmance status were bserved with bevacizumab; hwever, the rate f adverse events was higher with bevacizumab than with placeb A randmized trial f bevacizumab fr newly diagnsed gliblastma Gilbert MR et al. N Engl J Med. 2014;370(8):699 Regimen raditherapy (60 Gy) and daily temzlmide. Treatment with bevacizumab r placeb began during week 4 f raditherapy and was cntinued fr up t 12 cycles f maintenance chemtherapy. At disease prgressin, the assigned treatment was revealed, and bevacizumab therapy culd be initiated r cntinued Primary Endpint designed t detect a 25% reductin in the risk f death and a 30% reductin in the risk f prgressin r death, the tw cprimary end pints, with the additin f bevacizumab. Size (N) 637 patients Results OS: n statistical difference (15.7 mnths Bev. vs mnths placeb) Median PFS: 10.7 mnths (Bev) vs. 7.3 mnths (placeb) HR0.79 Txicity Bev. grup had mre adverse events (myelsuppresin, HTN, thrmbemblic disease, wund dehiscence, fatigue, visceral perfratin, serius hemrrhage) Cnclusin First-line use f bevacizumab did nt imprve verall survival in patients with newly diagnsed gliblastma. Prgressin-free survival was prlnged but did nt reach the prespecified imprvement target

16 D) REFERENCES - Canadian Cancer Statisitics Wng E. et al. Clinical presentatin and diagnsis f brain tumrs. In: UpTDate, Pst TW (Ed), UpTDate, Waltham, MA. (Accessed n Nvember 8, 2015.) - Batchelr T. Initial pstperative therapy fr gliblastma and anaplastic astrcytma. In: UpTDate, Pst TW (Ed), UpTDate, Waltham, MA. (Accessed n December 17, 2015.) - Yan H et al. IDH1 and IDH2 Mutatins in Glimas. N Engl J Med. 2009; 360: NCCN Guidelines Versin Central Nervus System Cancers - BC Cancer Agency Clinical Practice Guideline fr Neur-Onclgy - Oren JZ et al. Treatment f elderly patients with gliblastma a systematic evidence-based analysis JAMA Neurl. 72(5): Batchelr T. et al. Management f recurrent high-grade glimas. In: UpTDate, Pst TW (Ed), UpTDate, Waltham, MA. (Accessed n Nvember 11, 2015.) - Chang, S.M et al. Patterns f Care fr Adults with Newly Diagnsed Malignant Glima. JAMA. 2005; 295(5):