Radioterapia no Tratamento dos Gliomas de Baixo Grau

Transcription

1 Radioterapia no Tratamento dos Gliomas de Baixo Grau Dr. Luis Souhami University Montreal - Canada

2 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

3 LGG - Presentation Usually 2 nd and 4 th decades of life Seizure is most common symptom Mental status changes Headaches Focal neurological deficits

4 Imaging

5 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

6 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!!

7 Randomized trials in LGG EORTC Timing of RT Observation vs. Post-op RT (54 Gy) EORTC 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

8 Timing of RT Dose Alone or combined? What have we learned from these trials?

9 Timing of Radiation Therapy One randomized trial EORTC ( ) 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

10 EORTC 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

11 Is higher RT dose better? 2 Randomized Trials EORTC NCCTG/RTOG/ECOG

12 EORTC 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

13 EORTC Karim ABMF et al. IJROBP 1996

14 NCCTG/RTOG/ECOG Shaw E et al. J Clin Oncol 2002 Completely (15%) and incompletely resected 211 patients ( ) Pathology centrally reviewed Median follow-up 6.4 yrs LGG Randomize 50.4 Gy/28 fxs 64.8 Gy/36 fxs

15 NCCTG/RTOG/ECOG Shaw E et al. J Clin Oncol 2002 Overall Survival Progression-Free Survival Jenkins Cancer Res 2006

16 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

17 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

18 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) Bauman s Classification 2 Low risk High risk 1 Pignatti F et al JCO Bauman G et al IJROBP 1999

19 Exploring Risk Factors RTOG 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

20 RTOG 9802 Low Risk - Observation Neurosurgeon-defined GTR Age <40 Overall Survival 93% Shaw E et al. J Neurosurg 2008

21 RTOG 9802 Low-risk LGG Post-op Observation Progression-free Survival 43% Shaw E et al. J Neurosurg 2008

22 RTOG 9802 Low-risk LGG Post-op Observation Neurosurgeon-defined GTR Age < 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 year PFS 48% for all pts

23 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

24 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

25 Is 1p/19q co-deletion a marker for RT outcome? S u r v i v a l Jenkins et al. Cancer Res 2006

26 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

27 Planning Details T1 Gado + FLAIR CTV + 2 cm

28 Planning Details

29 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

30 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