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1、management of low grade gliomasrobert r johnson, m.d.department of radiation oncologyjuly 15, 2010table of contentsbackgroundpathological classificationmolecular featurespresentationtreatmenttechniquebackgroundslow-growing tumors10% of primary brain tumors in adults20-25% of gliomas2000 cases/year i
2、n u.s.divided into:pilocytic astrocytomadiffusely infiltrating gliomabackgroundpilocytic 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 resectionbackground
3、diffusely infiltrating glioma3rd-4th decade of life20 years earlier than high-grade gliomasslow growing but eventually fatal80% transform to high-gradehistological subtypesastrocytoma 50% fibrillaryprotoplasmicgemistocyticbehaves more like anaplastic astrocytomaoligodendroglioma 28%oligoastrocytoma
4、22%prognosis42,688 patients diagnosed between 1995-2006astrocytoma5-year survival 47%oligoastrocytoma5-year survival 57%oligodendroglioma5-year survival 79%http:/cbtrus.org/2010-NPCR-SEER/Table23.pdfpathological classificationwho gradingI: slow-growing, non-malignantpilocytic astrocytomaII: relative
5、ly slow-growing, can recur as higher-grade tumorastrocytoma, oligodendroglioma, oligoastrocytomapathological classificationst anne-mayo classificationbased on 4 criteria:nuclear atypiamitosesendothelial proliferationnecrosisgrade I: 0/4pilocytic astrocytomagrade II: 1/4astrocytoma, oligodendroglioma
6、, oligoastrocytomamolecular featuresploidybetter prognosis with diploid relative to aneuploidproliferationbetter prognosis with ki-67 index 60randomized to 54 gy/30 fractions vs observation and radiation at progressionvan den bent et al. lancet 2005;366:985-990.eortc 22485eortc 22485eortc 2248565% p
7、atients in observation group treated with radiation at recurrencemedian survival after recurrence 3.4 years vs 1.0 years favoring observation group70% histologically confirmed recurrences high-gradeno quality of life studyeortc 22485conclusionsno difference in overall survival for early vs delayed r
8、adiotherapylonger time to recurrence with early rtunknown if rt or recurrence is worse for quality of lifeseizures at 1 year25% with rt, 41% with observationP = 0.03eortc 22484379 patients with resected or biopsied low-grade gliomainclusion criteriasupratentorial low-grade gliomaincompletely resecte
9、d pilocytic astrocytoma16-65 yearskarnofsky 60randomized to 45 gy/25 fractions vs 59.4 gy/33 fractionskarim et al. ijrobp 1996; 36:549-556.eortc 224845 year os 58% vs 59%5 year pfs 47% vs 50%eortc 22484interesting subgroup analysesextent of resectionsize of tumoreortc 22484outcome analyzed by extent
10、 of resectionsignificant improvements in os and pfs with more extensive surgeryno dose responseeortc 22484eortc 22484eortc 22484acute toxicity more common in high-dose arm15% vs 8% required 1 week breakno difference in late toxicityno radionecrosis in either armeortc 22484conclusionsno dose response
11、 above 45 gyprognostic importance ofextent of resectiontumor sizehistologyastrocytoma worstneurological deficitseortc 22484/22485poor prognostic variablesage 40tumor 6 cmtumor crossing midlineastrocytoma histologyneurological deficits0-2 = low risk, median survival 7.7 years 3 = high risk, median su
12、rvival 3.2 yearsncctg 86-72-51203 patients with resected or biopsied low-grade gliomainclusion criteriasupratentorial low-grade gliomapilocytic astrocytoma excluded 18 yearsrandomized to 50.4 gy/28 fractions vs 64.8 gy/36 fractionsshaw et al. jco 2002;20:2267-2276.ncctg 86-72-51ncctg 86-72-51toxicit
13、ygrade 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 dosencctg-86-72-51conclusionsno dose response above 50.4 gyhigher severe toxicity with high doseprognostic importance ofextent of resectiontumor size
14、histologyastrocytoma worstageradiationconclusionsno difference in survival with post-op rt vs rt at progressionimproved pfsno dose response above 45-50 gyincreased toxicity with higher doseage, histology, tumor size, extent of resection all predict outcomechemotherapyno established role2 trials repo
15、rted encouraging results with ccnuneither significantpcv and temozolomide also been testedccnuswograndomized 60 patients with incompletely excised low-grade glioma to 55 gy +/- concurrent ccnumedian survival favored chemo arm7.4 years vs 4.5 yearsnot significantprematurely closed due to slow accrual
16、possible benefit if adequately poweredeyre et al. j neurosurg. 1993.pcvrtog 98-023 armed trialarm 1: low risk (age 40, subtotal resection or biopsy)randomized to 54 gy +/- 6 cycles adjuvant pcvprocarbazine, ccnu, vincristinepcvrtog 98-02 contdpreliminary results presented at asco in 2006temozolomide
17、significant survival benefit when used concurrently with radiotherapy in glioblastoma multiformestupp trialeasy administrationgood toxicity profiletemozolomide44 patients with newly diagnosed oligoastrocytoma or oligodendrogliomarecurrent low-grade glioma75mg/m2/day7 weeks on, 4 weeks off6 cycles or
18、 tumor progressionkesari et al. clinical cancer research 2009;15:330-337temozolomide95% disease control rate20% partial response75% stable disease72 month median survival38 month median progression-free survivaltemozolomidesignificantly better suvival formgmt promoter methylation 72 months with, 29
19、months without1p/19q co-deletion 72 months with, 27 months withouttoxicity mildtemozolomidetemozolomideduke university phase II trialrecurrent low-grade glioma46 patients given 12 cycles of temozolomidestop early if progression96% disease control rate24% complete response37% partial response35% stab
20、le diseasequinn et al. jco 2003;21:646-651.median 22 monthschemotherapyconclusionsccnu, pcv, temozolomide have all shown some promiseadded toxicitytemozolomide has most promisesuccess in gbmmild toxicity profilemost likely to benefit patients with co-deletion of 1p and 19q?oligodendrogliomasequelae
21、of treatmentacute toxicity (to radiotherapy) includesfatigueheadachenausea/vomitingscalp irritationhair lossotitis externasequelae of treatmentlate toxicityradionecrosisuncommon due to low dose/fractionmalignant degenerationnot seen with pilocytic astrocytoma or diffusely infiltrating gliomasneuroco
22、gnitive declineneurocognitive declinepotential causesradiotherapychemotherapytumor progressionvascular diseasedepressionnutritional deficiencymedicationsneurocognitive decline20 patients from ncctg 86-72-51 followed prospectively with extensive psychometric testing10 from 50.4 gy arm, 10 from 64.8 g
23、y armevaluated before rt and at 18 month intervals for 5 yearslaack et al. ijrobp 2005;63:1175-1183.neurocognitive declinebaseline scores below age-specific averagesscores improved at first post-treatment evaluationno evidence of neurocognitive decline with 3 years of follow-upneurocognitive decline
24、prospective study of 26 patients treated for low-grade brain tumors46-56 gy in 1.8-2 gy fractionsexcluded patients with pre-existing vascular diseasediabeteshypertensioncoronary artery diseasearmstrong et al. neurology;59:40-48.neurocognitive declinearmstrong et al, contd4-hour neuropsychological te
25、sting atbaseline (after surgery, before rt)yearly for 6 yearsmri evaluated forwhite matter diseaseatrophyneurocognitive declinearmstrong et al, contdmild decline in visual learningafter 5 yearsimprovement in multiple parametersno correlation between cognitive decline and mri changesneurocognitive de
26、clineneurocognitive declinetumor progression probably most significant causeother factors do contributechemotherapyradiotherapynon-treatment relatedpatients live longde-escalation of therapy worthy of further studyfuture directionsinteresting randomized trials evaluatingrt alonetemozolomide alonert
27、and concurrent temozolomideeortc 22033phase III trial of patients withprogressive diseaseuncontrolled seizures despite anti-convulsantsneurological symptomsrandomized to standard dose rt vs temozolomidepfs and os are primary endpointsecog-e3f05phase III trial of patients withprogressive diseaseuncon
28、trolled neurological symptomsage 40randomized to 50.4 gy +/- concurrent and adjuvant temozolomidepfs and os are primary endpointsconclusionslow-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 declinequestions?
