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1、management of low grade gliomas,robert r johnson,m.d.department of radiation oncologyjuly 15,2010,table of contents,backgroundpathological classificationmolecular featurespresentationtreatmenttechnique,background,slow-growing tumors10%of primary brain tumors in adults20-25%of gliomas2000 cases/year
2、in u.s.divided into:pilocytic astrocytomadiffusely infiltrating glioma,background,pilocytic astrocytomamore common in children(jpa)cerebellumdo occur in young adultslow gradeeven after recurrencecured by surgery 90%long-term survival after complete resection70-80%after incomplete resection,backgroun
3、d,diffusely infiltrating glioma3rd-4th decade of life20 years earlier than high-grade gliomasslow growing but eventually fatal80%transform to high-grade,histological subtypes,astrocytoma 50%fibrillaryprotoplasmicgemistocyticbehaves more like anaplastic astrocytomaoligodendroglioma 28%oligoastrocytom
4、a 22%,prognosis,42,688 patients diagnosed between 1995-2006astrocytoma5-year survival 47%oligoastrocytoma5-year survival 57%oligodendroglioma5-year survival 79%,http:/cbtrus.org/2010-NPCR-SEER/Table23.pdf,pathological classification,who gradingI:slow-growing,non-malignantpilocytic astrocytomaII:rela
5、tively slow-growing,can recur as higher-grade tumorastrocytoma,oligodendroglioma,oligoastrocytoma,pathological classification,st anne-mayo classificationbased on 4 criteria:nuclear atypiamitosesendothelial proliferationnecrosisgrade I:0/4pilocytic astrocytomagrade II:1/4astrocytoma,oligodendroglioma
6、,oligoastrocytoma,molecular features,ploidybetter prognosis with diploid relative to aneuploidproliferationbetter prognosis with ki-67 index 3%co-deletion of 1p and 19q,co-deletion of 1p/19q,found in 70-75%oligodendroglioma35-40%oligoastrocytomararely in pure astrocytomafavorable prognosis139 sample
7、s of 80 patients with low-grade gliomamedian survival:15 years with co-deletion5 years withoutmore likely to respond to chemotherapy,presentation,imaging,pilocytic astrocytomawell-circumscribedcysticcontrast-enhancingvasogenic edema is rare,imaging,diffusely infiltrating gliomactdiffuse,non-enhancin
8、gcalcifications with oligodendroglioma,imaging,diffusely infiltrating gliomamrihypointense and non-enhancing on t1hyperintense on t2,treatment,pilocytic astrocytomamore amenable to total resectionwell-circumscribedclose follow-up after surgery70-80%long-term survival after subtotal resectiontransfor
9、mation to high-grade glioma very rareadjuvant radiotherapy not typically offered50-55 gy for recurrent/unresectable disease,pilocytic astrocytoma,20 adults from ncctg 86-72-51 followed prospectively3 patients irradiated after biopsy50.4 gy17 patients observed after subtotal or gross total resection,
10、brown et al.ijrobp 2004;58:1153-1160.,pilocytic astrocytoma,pilocytic astrocytoma,pilocytic astrocytoma,excellent prognosis irrespective of treatment modalitydistinctly different behavior from diffusely infiltrating gliomas10-year survival 95%vs 17%in ncctg 86-72-51,diffusely infiltrating glioma,sur
11、geryradiationchemotherapy,surgery,usually performed firstestablish diagnosistumor debulkingtotal resection uncommon due to diffuse infiltrationrarely curativeretrospective data suggests benefit for total/subtotal resectionmost accurate pathological assessment,radiation,3 randomized trials have asses
12、sed timing and dose of adjuvant radiotherapyeortc 22485immediate vs delayedeortc 2248445 gy vs 59.4 gyncctg 86-72-5150.4 gy vs 64.8 gy,eortc 22485,314 patients with resected or biopsied low-grade gliomainclusion criteriasupratentorial low-grade glioma16-65 yearskarnofsky 60randomized to 54 gy/30 fra
13、ctions vs observation and radiation at progression,van den bent et al.lancet 2005;366:985-990.,eortc 22485,eortc 22485,eortc 22485,65%patients in observation group treated with radiation at recurrencemedian survival after recurrence 3.4 years vs 1.0 years favoring observation group70%histologically
14、confirmed recurrences high-gradeno quality of life study,eortc 22485,conclusionsno difference in overall survival for early vs delayed radiotherapylonger time to recurrence with early rtunknown if rt or recurrence is worse for quality of lifeseizures at 1 year25%with rt,41%with observationP=0.03,eor
15、tc 22484,379 patients with resected or biopsied low-grade gliomainclusion criteriasupratentorial low-grade gliomaincompletely resected pilocytic astrocytoma16-65 yearskarnofsky 60randomized to 45 gy/25 fractions vs 59.4 gy/33 fractions,karim et al.ijrobp 1996;36:549-556.,eortc 22484,5 year os 58%vs
16、59%,5 year pfs 47%vs 50%,eortc 22484,interesting subgroup analysesextent of resectionsize of tumor,eortc 22484,outcome analyzed by extent of resectionsignificant improvements in os and pfs with more extensive surgeryno dose response,eortc 22484,eortc 22484,eortc 22484,acute toxicity more common in h
17、igh-dose arm15%vs 8%required 1 week breakno difference in late toxicityno radionecrosis in either arm,eortc 22484,conclusionsno dose response above 45 gyprognostic importance ofextent of resectiontumor sizehistologyastrocytoma worstneurological deficits,eortc 22484/22485,poor prognostic variablesage
18、 40tumor 6 cmtumor crossing midlineastrocytoma histologyneurological deficits0-2=low risk,median survival 7.7 years 3=high risk,median survival 3.2 years,ncctg 86-72-51,203 patients with resected or biopsied low-grade gliomainclusion criteriasupratentorial low-grade gliomapilocytic astrocytoma exclu
19、ded 18 yearsrandomized to 50.4 gy/28 fractions vs 64.8 gy/36 fractions,shaw et al.jco 2002;20:2267-2276.,ncctg 86-72-51,ncctg 86-72-51,toxicitygrade 3-5 toxicity seen in 13%patients on both armsgrade 3-5 severe toxicityradionecrosis and encephalitis5%vs 2.5%at 2 yearsmore common with high dose,ncctg
20、-86-72-51,conclusionsno dose response above 50.4 gyhigher severe toxicity with high doseprognostic importance ofextent of resectiontumor sizehistologyastrocytoma worstage,radiation,conclusionsno difference in survival with post-op rt vs rt at progressionimproved pfsno dose response above 45-50 gyinc
21、reased toxicity with higher doseage,histology,tumor size,extent of resection all predict outcome,chemotherapy,no established role2 trials reported encouraging results with ccnuneither significantpcv and temozolomide also been tested,ccnu,swograndomized 60 patients with incompletely excised low-grade
22、 glioma to 55 gy+/-concurrent ccnumedian survival favored chemo arm7.4 years vs 4.5 yearsnot significantprematurely closed due to slow accrualpossible benefit if adequately powered,eyre et al.j neurosurg.1993.,pcv,rtog 98-023 armed trialarm 1:low risk(age 40,subtotal resection or biopsy)randomized t
23、o 54 gy+/-6 cycles adjuvant pcvprocarbazine,ccnu,vincristine,pcv,rtog 98-02 contdpreliminary results presented at asco in 2006,temozolomide,significant survival benefit when used concurrently with radiotherapy in glioblastoma multiformestupp trialeasy administrationgood toxicity profile,temozolomide
24、,44 patients with newly diagnosed oligoastrocytoma or oligodendrogliomarecurrent low-grade glioma75mg/m2/day7 weeks on,4 weeks off6 cycles or tumor progression,kesari et al.clinical cancer research 2009;15:330-337,temozolomide,95%disease control rate20%partial response75%stable disease72 month media
25、n survival38 month median progression-free survival,temozolomide,significantly better suvival formgmt promoter methylation 72 months with,29 months without1p/19q co-deletion 72 months with,27 months withouttoxicity mild,temozolomide,temozolomide,duke university phase II trialrecurrent low-grade glio
26、ma46 patients given 12 cycles of temozolomidestop early if progression96%disease control rate24%complete response37%partial response35%stable disease,quinn et al.jco 2003;21:646-651.,median 22 months,chemotherapy,conclusionsccnu,pcv,temozolomide have all shown some promiseadded toxicitytemozolomide
27、has most promisesuccess in gbmmild toxicity profilemost likely to benefit patients with co-deletion of 1p and 19q?oligodendroglioma,sequelae of treatment,acute toxicity(to radiotherapy)includesfatigueheadachenausea/vomitingscalp irritationhair lossotitis externa,sequelae of treatment,late toxicityra
28、dionecrosisuncommon due to low dose/fractionmalignant degenerationnot seen with pilocytic astrocytoma or diffusely infiltrating gliomasneurocognitive decline,neurocognitive decline,potential causesradiotherapychemotherapytumor progressionvascular diseasedepressionnutritional deficiencymedications,ne
29、urocognitive decline,20 patients from ncctg 86-72-51 followed prospectively with extensive psychometric testing10 from 50.4 gy arm,10 from 64.8 gy armevaluated before rt and at 18 month intervals for 5 years,laack et al.ijrobp 2005;63:1175-1183.,neurocognitive decline,baseline scores below age-speci
30、fic averagesscores improved at first post-treatment evaluationno evidence of neurocognitive decline with 3 years of follow-up,neurocognitive decline,prospective study of 26 patients treated for low-grade brain tumors46-56 gy in 1.8-2 gy fractionsexcluded patients with pre-existing vascular diseasedi
31、abeteshypertensioncoronary artery disease,armstrong et al.neurology;59:40-48.,neurocognitive decline,armstrong et al,contd4-hour neuropsychological testing atbaseline(after surgery,before rt)yearly for 6 yearsmri evaluated forwhite matter diseaseatrophy,neurocognitive decline,armstrong et al,contdmi
32、ld decline in visual learningafter 5 yearsimprovement in multiple parametersno correlation between cognitive decline and mri changes,neurocognitive decline,neurocognitive decline,tumor progression probably most significant causeother factors do contributechemotherapyradiotherapynon-treatment related
33、patients live longde-escalation of therapy worthy of further study,future directions,interesting randomized trials evaluatingrt alonetemozolomide alonert and concurrent temozolomide,eortc 22033,phase III trial of patients withprogressive diseaseuncontrolled seizures despite anti-convulsantsneurologi
34、cal symptomsrandomized to standard dose rt vs temozolomidepfs and os are primary endpoints,ecog-e3f05,phase III trial of patients withprogressive diseaseuncontrolled neurological symptomsage 40randomized to 50.4 gy+/-concurrent and adjuvant temozolomidepfs and os are primary endpoints,conclusions,low-grade glioma slow-growing but progressive diseasesurgery,radiotherapy,chemotherapy all have roleoptimal sequence,duration unknownpatients live long enough to experience toxicity of treatmenttumor progression most important cause of neurocognitive decline,questions?,
