Radioterapia no Tratamento dos Gliomas de Baixo Grau Dr. Luis Souhami University Montreal - Canada
Low Grade Gliomas Relatively rare Heterogeneous, slow growing tumors WHO Classification Grade I Pilocytic astrocytoma Xanthoastrocytoma Pleomorphic Ganglioglioma (PXA) Dysembrioplastic Neuroepithelial Tumor (DNET) Grade II Astrocytoma Oligodendroglioma Oligoastrocytoma
LGG - Presentation Usually 2 nd and 4 th decades of life Seizure is most common symptom Mental status changes Headaches Focal neurological deficits
Imaging
Evidence-based Management Surgical resection Maximum safe resection Biopsy or observation in certain circumstances Role of Radiation Therapy Post-operative or delayed radiation therapy Sophisticated planning and delivery Systemic therapy
Does post-op RT make any difference? Post-op RT Shaw EG et al. J Neurosurg 1989 Bahary J-P et al. J Neurooncol 1996 YES!! NO!!
Randomized trials in LGG EORTC 22844 Timing of RT Observation vs. Post-op RT (54 Gy) EORTC 22845 RT Dose Low (45 Gy) vs. High dose (59.4 Gy) NCCTG/RTOG/ECOG RT Dose Low (50.4 Gy) vs. High dose (64.8 Gy) RTOG 8402 Systemic therapy RT (54 Gy) vs. RT + PCV
Timing of RT Dose Alone or combined? What have we learned from these trials?
Timing of Radiation Therapy One randomized trial EORTC 22845 (1986-1997) Surgery RT Obs. (54 Gy) 312 pts: stratified by center, histology and resection Overall Survival Progression-Free Survival van den Bent M et al. Lancet 2005
EORTC 22845 Further Details Grossly (42%) and partially resected tumors Higher grade 26% (central review) CT scan-based No sub-group analysis No QoL data 65% (crude) of patients required RT No difference between groups for cognitive deficits
Is higher RT dose better? 2 Randomized Trials EORTC 22844 NCCTG/RTOG/ECOG
EORTC 22844 Karim ABMF et al. IJROBP 1996 Completely and incompletely resected LGGs 379 patients; Median follow-up 74 mos LGG Randomize 45 Gy/25 fxs 59.4 Gy/33 fxs
EORTC 22844 Karim ABMF et al. IJROBP 1996
NCCTG/RTOG/ECOG Shaw E et al. J Clin Oncol 2002 Completely (15%) and incompletely resected 211 patients (1986-1994) Pathology centrally reviewed Median follow-up 6.4 yrs LGG Randomize 50.4 Gy/28 fxs 64.8 Gy/36 fxs
NCCTG/RTOG/ECOG Shaw E et al. J Clin Oncol 2002 Overall Survival Progression-Free Survival Jenkins Cancer Res 2006
What Have We Learned From Randomized Trials? Immediate post-op RT does not prolong overall survival PFS is prolonged Neurocognitive deficits similar in treated and untreated population (poorly tested!) No radiation dose-response (45 to 64.9 Gy) Neuro toxicity increased in higher dose group NCCTG/RTOG Trial
What Have We Learned From Randomized Trials? Most failures within RT volume Well-defined prognostic factors Age Histology Resection extension Size Neurologic function Midline crossing
Risk Grouping EORTC Classification 1 High Risk* Age > 40 Pre-op tumor size 6.0 cm Tumor crosses midline Astrocytoma dominant Pre-op NF function >1 *Pt must have at least 3 factors Score MS(yr) 0 9.2 5 0.7 Bauman s Classification 2 Low risk High risk 1 Pignatti F et al JCO 2002 2 Bauman G et al IJROBP 1999
Exploring Risk Factors RTOG 98-02 trial Low-Risk Group (age <40, complete resection) Surgery Observation High-Risk Group (age >40, sub-total or biopsy) Can chemotherapy improve outcomes? Surgery Randomize RT alone (54 Gy) RT + PCV 6 cycles
RTOG 9802 Low Risk - Observation Neurosurgeon-defined GTR Age <40 Overall Survival 93% Shaw E et al. J Neurosurg 2008
RTOG 9802 Low-risk LGG Post-op Observation Progression-free Survival 43% Shaw E et al. J Neurosurg 2008
RTOG 9802 Low-risk LGG Post-op Observation Neurosurgeon-defined GTR Age <40 111 pts with pre + post MRI Size <4 cm, oligo <1 cm residual Imaging Residual Residual MRI % Pts % with recurrence <1 cm 59% 26% Size 4 cm, astro 1 cm, residual Other combinations of prognostic factors 1-2 cm 32% 68% >2 cm 9% 89% Shaw E et al. J Neurosurg 2008 5-year PFS 48% for all pts
RTOG 9802 Combined Therapy High Risk Group (age >40; incomplete resection) Surgery Randomize RT Alone (54 Gy) RT + PCV 6 cycles RT alone (54 Gy) p=0.13 p=0.005 Shaw E. et al. J Clin Oncol 2012
Molecular Changes in LGGs Methylation status of MGMT gene Impact on temozolomide therapy? IDH1, 2 improved PFS: 29.5 vs 6 months Everhard et al. Ann Neurol 2006 Loss of heterozygosity of 1p 19q chromosomes better prognosis? 1p19q LOH mediated by a translocation t(1;19)(q10;p10) 1p19q LOH associated with improved treatment response/survival in Anaplastic Oligos? low grade oligo 1p32 1q42 19q13 19p13
Is 1p/19q co-deletion a marker for RT outcome? S u r v i v a l Jenkins et al. Cancer Res 2006
Experience: Pure Low Grade Oligodendrogliomas 69 patients 1p19q LOH 55% Methylated MGMT 54% Overall survival Progression-free Survival LOH only significant in univariate analysis for overall survival El-Hateer, Souhami, Roberge et al. J Neurosurg 2009
Planning Details T1 Gado + FLAIR CTV + 2 cm
Planning Details
Conclusions Not all LGGs behave in the same manner Low-risk: 5-yr OS = 93% 5-yr PFS = 50% High-risk: 5-yr OS = 66% 5-yr PFS = 50% Complete surgical resection, young age and oligo histopathology are the best prognostic factors Maximum safe surgical resection Role of RT not clearly defined RT improves PFS but has no impact on overall survival No dose-response effect
Future Directions Improved neurosurgical techniques MRS Intraoperative techniques Functional mapping (Duffau, Berger) Molecular profiling 1p/19q LOH Methylation status, IDH1-2 Other molecular markers Three on-going/closed trials RTOG 0424 (closed) Phase II: RT + TZM high-risk LGGs EORTC/NCIC (closed) Phase III: RT vs TZM (stratified by 1p loss) Intergroup (open) Phase III: RT ± TMZ