1、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 20
2、00 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 inc
3、omplete 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
4、 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%,http:/cbtrus.org/2010-NPCR-SEER/Table23.pdf,pathological classification,who grading I: slow-gro
5、wing, 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
6、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 3% co-deletion of 1p and 19q,co-deletion of 1p/19q,found in 70-75% oligodendroglioma 35-4
7、0% oligoastrocytoma rarely in pure astrocytoma favorable prognosis 139 samples of 80 patients with low-grade glioma median survival: 15 years with co-deletion 5 years without more likely to respond to chemotherapy,presentation,imaging,pilocytic astrocytoma well-circumscribed cystic contrast-enhancin
8、g vasogenic edema is rare,imaging,diffusely infiltrating glioma ct diffuse , non-enhancing calcifications with oligodendroglioma,imaging,diffusely infiltrating glioma mri hypointense and non-enhancing on t1 hyperintense on t2,treatment,pilocytic astrocytoma more amenable to total resection well-circ
9、umscribed close follow-up after surgery 70-80% long-term survival after subtotal resection transformation to high-grade glioma very rare adjuvant radiotherapy not typically offered 50-55 gy for recurrent/unresectable disease,pilocytic astrocytoma,20 adults from ncctg 86-72-51 followed prospectively
10、3 patients irradiated after biopsy 50.4 gy 17 patients observed after subtotal or gross total resection,brown et al. ijrobp 2004;58:1153-1160.,pilocytic astrocytoma,pilocytic astrocytoma,pilocytic astrocytoma,excellent prognosis irrespective of treatment modality distinctly different behavior from d
11、iffusely infiltrating gliomas 10-year survival 95% vs 17% in ncctg 86-72-51,diffusely infiltrating glioma,surgery radiation chemotherapy,surgery,usually performed first establish diagnosis tumor debulking total resection uncommon due to diffuse infiltration rarely curative retrospective data suggest
12、s benefit for total/subtotal resection most accurate pathological assessment,radiation,3 randomized trials have assessed timing and dose of adjuvant radiotherapy eortc 22485 immediate vs delayed eortc 22484 45 gy vs 59.4 gy ncctg 86-72-51 50.4 gy vs 64.8 gy,eortc 22485,314 patients with resected or
13、biopsied low-grade glioma inclusion criteria supratentorial low-grade glioma 16-65 years karnofsky 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 treate
14、d 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 re
15、currence 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 astrocy
16、toma 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 re
17、section 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 re
18、sponse 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 =
19、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 8
20、6-72-51,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 im
21、portance 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
22、 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
23、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
24、,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 oligod
25、endroglioma 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 surv
26、ival,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 temozol
27、omide 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
28、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
29、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,neu
30、rocognitive 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-sp
31、ecific 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 di
32、sease 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,arm
33、strong 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 radio
34、therapy non-treatment related patients live long de-escalation of therapy worthy of further study,future directions,interesting randomized trials evaluating rt alone temozolomide alone rt and concurrent temozolomide,eortc 22033,phase III trial of patients with progressive disease uncontrolled seizur
35、es despite anti-convulsants neurological symptoms randomized to standard dose rt vs temozolomide pfs and os are primary endpoints,ecog-e3f05,phase III trial of patients with progressive disease uncontrolled neurological symptoms age 40 randomized to 50.4 gy +/- concurrent and adjuvant temozolomide p
36、fs and os are primary endpoints,conclusions,low-grade glioma slow-growing but progressive disease surgery, radiotherapy, chemotherapy all have role optimal sequence, duration unknown patients live long enough to experience toxicity of treatment tumor progression most important cause of neurocognitive decline,questions?,
