grade glioma university of louisville低级别胶质瘤路易斯威尔大学课件

management of low grade gliomas robert r johnson, m.d. department of radiation oncology july 15, 2010 table of contents background pathological classification molecular features presentation treatment technique background slow-growing tumors 10% of primary brain tumors in adults 20-25% of gliomas 2000 cases/year in u.s. divided into: pilocytic astrocytoma diffusely infiltrating glioma background pilocytic astrocytoma more common in children (jpa) cerebellum do occur in young adults low grade even after recurrence cured by surgery 90% long-term survival after complete resection 70-80% after incomplete resection background diffusely infiltrating glioma 3rd-4th decade of life 20 years earlier than high-grade gliomas slow growing but eventually fatal 80% transform to high-grade histological subtypes astrocytoma 50% fibrillary protoplasmic gemistocytic behaves more like anaplastic astrocytoma oligodendroglioma 28% oligoastrocytoma 22% prognosis 42,688 patients diagnosed between 1995- 2006 astrocytoma 5-year survival 47% oligoastrocytoma 5-year survival 57% oligodendroglioma 5-year survival 79% /2010-NPCR-SEER/Table23.pdf pathological classification who grading I: slow-growing, non-malignant pilocytic astrocytoma II: relatively slow-growing, can recur as higher- grade tumor astrocytoma, oligodendroglioma, oligoastrocytoma pathological classification st anne-mayo classification based on 4 criteria: nuclear atypia mitoses endothelial proliferation necrosis grade I: 0/4 pilocytic astrocytoma grade II: 1/4 astrocytoma, oligodendroglioma, oligoastrocytoma molecular features ploidy better prognosis with diploid relative to aneuploid proliferation better prognosis with ki-67 index 60 randomized to 54 gy/30 fractions 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 recurrence median survival after recurrence 3.4 years vs 1.0 years favoring observation group 70% histologically confirmed recurrences high-grade no quality of life study eortc 22485 conclusions no difference in overall survival for early vs delayed radiotherapy longer time to recurrence with early rt unknown if rt or recurrence is worse for quality of life seizures at 1 year 25% with rt, 41% with observation P = 0.03 eortc 22484 379 patients with resected or biopsied low- grade glioma inclusion criteria supratentorial low-grade glioma incompletely resected pilocytic astrocytoma 16-65 years karnofsky 60 randomized 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 59%5 year pfs 47% vs 50% eortc 22484 interesting subgroup analyses extent of resection size of tumor eortc 22484 outcome analyzed by extent of resection significant improvements in os and pfs with more extensive surgery no dose response eortc 22484 eortc 22484 eortc 22484 acute toxicity more common in high-dose arm 15% vs 8% required 1 week break no difference in late toxicity no radionecrosis in either arm eortc 22484 conclusions no dose response above 45 gy prognostic importance of extent of resection tumor size histology astrocytoma worst neurological deficits eortc 22484/22485 poor prognostic variables age 40 tumor 6 cm tumor crossing midline astrocytoma histology neurological deficits 0-2 = 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 glioma inclusion criteria supratentorial low-grade glioma pilocytic astrocytoma excluded 18 years randomized 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 toxicity grade 3-5 toxicity seen in 13% patients on both arms grade 3-5 severe toxicity radionecrosis and encephalitis 5% vs 2.5% at 2 years more common with high dose ncctg-86-72-51 conclusions no dose response above 50.4 gy higher severe toxicity with high dose prognostic importance of extent of resection tumor size histology astrocytoma worst age radiation conclusions no difference in survival with post-op rt vs rt at progression improved pfs no dose response above 45-50 gy increased toxicity with higher dose age, histology, tumor size, extent of resection all predict outcome chemotherapy no established role 2 trials reported encouraging results with ccnu neither significant pcv and temozolomide also been tested ccnu swog randomized 60 patients with incompletely excised low-grade glioma to 55 gy +/- concurrent ccnu median survival favored chemo arm 7.4 years vs 4.5 years not significant prematurely closed due to slow accrual possible benefit if adequately powered eyre et al. j neurosurg. 1993. pcv rtog 98-02 3 armed trial arm 1: low risk (age 40, subtotal resection or biopsy) randomized to 54 gy +/- 6 cycles adjuvant pcv procarbazine, ccnu, vincristine pcv rtog 98-02 contd preliminary results presented at asco in 2006 temozolomide significant survival benefit when used concurrently with radiotherapy in glioblastoma multiforme stupp trial easy administration good toxicity profile temozolomide 44 patients with newly diagnosed oligoastrocytoma or oligodendroglioma recurrent low-grade glioma 75mg/m2/day 7 weeks on, 4 weeks off 6 cycles or tumor progression kesari et al. clinical cancer research 2009;15:330-337 temozolomide 95% disease control rate 20% partial response 75% stable disease 72 month median survival 38 month median progression-free survival temozolomide significantly better suvival for mgmt promoter methylation 72 months with, 29 months without 1p/19q co-deletion 72 months with, 27 months without toxicity mild temozolomide temozolomide duke university phase II trial recurrent low-grade glioma 46 patients given 12 cycles of temozolomide stop early if progression 96% disease control rate 24% complete response 37% partial response 35% stable disease quinn et al. jco 2003;21:646-651. median 22 months chemotherapy conclusions ccnu, pcv, temozolomide have all shown some promise added toxicity temozolomide has most promise success in gbm mild toxicity profile most likely to benefit patients with co-deletion of 1p and 19q? oligodendroglioma sequelae of treatment acute toxicity (to radiotherapy) includes fatigue headache nausea/vomiting scalp irritation hair loss otitis externa sequelae of treatment late toxicity radionecrosis uncommon due to low dose/fraction malignant degeneration not seen with pilocytic astrocytoma or diffusely infiltrating gliomas neurocognitive decline neurocognitive decline potential causes radiotherapy chemotherapy tumor progression vascular disease depression nutritional deficiency medications neurocognitive decline 20 patients from ncctg 86-72-51 followed prospectively with extensive psychometric testing 10 from 50.4 gy arm, 10 from 64.8 gy arm evaluated before rt and at 18 month intervals for 5 years laack et al. ijrobp 2005;63:1175-1183. neurocognitive decline baseline scores below age-specific averages scores improved at first post-treatment evaluation no evidence of neurocognitive decline with 3 years of follow-up neurocognitive decline prospective study of 26 patients treated for low-grade brain tumors 46-56 gy in 1.8-2 gy fractions excluded patients with pre-existing vascular disease diabetes hypertension coronary artery disease armstrong et al. neurology;59:40-48. neurocognitive decline armstrong et al, contd 4-hour neuropsychological testing at baseline (after surgery, before rt) yearly for 6 years mri evaluated for white matter disease atrophy neurocognitive decline armstrong et al, contd mild decline in visual learning after 5 years improvement in multiple parameters no correlation between cognitive decline and mri changes neurocognitive decline neurocognitive decline tumor progression probably most significant cause other factors do contribute chemotherapy radiotherapy non-treatment related patient