Low-Grade Astrocytoma of the CNS: Systemic Treatment Third International Neuro-Oncology Course São Paulo, Brazil 23 May 2014 John de Groot, MD Associate Professor, Neuro-Oncology UT MD Anderson Cancer Center Houston, Texas, USA
Disclosures Consulting Advisory Board: Genentech, Novartis, Celldex DSMB: VBL Therapeutics Consulting: Celldex, Deciphera Pharmaceuticals Research Support Sanofi-Aventis, AstraZeneca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmaceuticals
Outline Background Important molecular markers Treatment considerations Role of chemotherapy Treatment implications Conclusions and future directions
Is LGG benign? LGG are slow growing and indolent Average survival ranges from 5 to 10 years High rate of relapse, often as higher grade tumor Recurrence rate reported to be 40-70% Therefore, LGG (WHO Grade II) should be considered malignant
LGG Prognosis: Clinical Variables Factors that negatively affect survival: Age >40 years Astrocytic glioma Lesion >6 cm in diameter Midline shift Tumor crossing the midline Deficits before surgery Lead time bias (?) High risk group (>2), median OS 3.2 years Low risk group ( 2), median OS 7.7 7 years Caveats: CT era!! and No Molecular Markers Pignatti F, van den Bent M, Curran D, et al; EORTC Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 2002 Apr 15;20(8):2076-84
LGG Prognosis: Clinical Variables Large, multi-institutional i tit l cohort UCSF validated Preoperative prognostic scoring system Location of tumor in eloquent cortex KPS score 80 Age > 50 years Maximum tumor diameter > 4 cm Scoring system based on these factors was able to predict both OS and PFS in the validation set of patients. Chang EF, Clark A, Jensen RL, et al. Multiinstitutional validation of the UCSF Low-Grade Glioma Prognostic Scoring System. Clinical article. J Neurosurg 2009;111:203-210
MOLECULAR BASIS OF GLIOMAGENESIS Ohgaki H and Kleihues P, The definition of primary and secondary glioblastoma, CCR 2013.
LGG Prognosis: Molecular Profile 1p/19q LOH -- powerful and independent prognostic factor in primary and recurrent tumors Cairncross, et al. 1998. Fallon KB, Palmer CA, Roth KA, et al. Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas. J Neuropathol Exp Neurol 2004;63:314-322.
LGG: Treatment History 1970s-1990s: lack of consistent consensus on treatment t t approach Mid 1990s: organizational effort by RTOG to develop consensus Extensive literature review background for protocol 9802 XRT vs XRT PCV Late 1990s- early 2000s Impact of chromosomal analysis for 1p19q but still under evaluation Studies include both oligodendroglioma and astrocytoma!
LGG: Treatment Goals Prolong overall survival Prolong progression free survival Minimize morbidity from our treatments Prevent tumor enlargement and transformation
RTOG 98-02 Shaw EG, Berkey B, Coons SW, et al. Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 2008;109:835-841.
RTOG 98-02 OVERALL SURVIVAL Favorable: 93% 5-year OS Unfavorable: 66% 5-year OS PF SURVIVAL No difference (50%) Median PFS is 5 years Low risk: Age <40 years GTR (neurosurgeon determined) Low risk: Age <40 years, GTR (neurosurgeon determined) High risk: age >40 years, subtotal resection
RTOG 98-02: Observation Arm 111 patients accrued PFS: 2 years 82% 5 years 48% Risk factors for progression Astrocytic or mixed histology Preop tumor > 4 cm Post op tumor > 1 cm Shaw EG et al J Neurosurg 109:835, 2008
RTOG 98-02 5 year PFS 70% 5 year PFS 13% Unfavorable Prognostic Factors: Astrocytoma/oligoastrocytoma* g y histology Preoperative tumor diameter >4 cm Imaging residual tumor >1 cm
RTOG 98-02: Randomized Treatment Arms Randomization: Radiation therapy: 54 Gy in 30 fractions Tumor volume based on post operative MRI 2 cm margin Radiation + PCV Radiation dose as above 6 cycles of procarbazine, CCNU, vincristine
RTOG 98-02 Results Addition of PCV increased PFS but not OS Beyond 2 years, the radiation + PCV showed both a survival and progression-free survival benefit Suggests a delayed benefit for chemotherapy Difference in toxicity: myelotoxicity y w/ chemotherapy Would this change with less toxic temozolomide?
Update: RTOG 98-02 From date of registration Patients alive at 2 years Shaw EG et al. JCO 2012;30:3065-3070
RTOG 98-02: Study Conclusions 5yr PFS is 70% in young adults with LGG who undergo neurosurgeon-determined GTR High-risk treated gliomas and untreated low risk gliomas progress at a similar rate Update: PCV + RT may improve overall survival* *Are these patients with oligodendroglioma? The addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up Prabhu RS, et al. J Clin Oncol 2014
LGG: Role of chemotherapy Chemotherapy must fit into the overall treatment plan which varies by several factors Patient characteristics: Age, logistics, general state of health and state of mind Tumor characteristics: Astrocytoma vs oligodendroglioma 1p/19q intact or co-deleted Extent of tumor resection Proliferative index Physician characteristics: most apparent factor! Aggressive, multimodality approach vs careful observation or somewhere in between
LGG: Chemotherapy data The literature varies regarding chemotherapy use: Stage of disease Neoadjuvant (preradiation, exclusive treatment) Adjuvant Recurrent disease Histology Astrocytoma vs OA vs oligodendroglioma vs combination
LGG: Chemotherapy Study No of patients Pathology Enhancement (%) Prior RT or chemotherapy Chemotherapy Regimen Response rate (%) 1 year PFS Buckner et al Soffieti et al Quinn et al 28 O, OA 46 No PCV 52 91 26 O,OA 73 Yes PCV 62 80 46 A, O, AA 70 Yes TMZ 61 76 Pace et al 43 A, O, AA 60 Yes TMZ 47 39 Brada et al Hoang Xuan et al Van den Bent et al 30 A, O, AA 0 No TMZ 10 > 90 60 O, OA 11 No TMZ 31 73 32 O, OA 100 Yes* TMZ 22 11 Table from: Gilbert and Lang, Neurol Clin 2007
EORTC 22041, Phase III RT (50.4 Gy) versus TMZ LGG: Ongoing Clinical Trials Primary end point: PFS Secondary end points: quality of life and cognitive function Stratification by 1p/19q status E3FO5 (2009): Phase III High risk XRT vs Stupp regimen EORTC 22033/26033 (2005): Phase III Newly diagnosed RT versus TMZ
LGG: Treatment Considerations Upfront Young patient <40, GTR,oligo, tumor diameter < 4 cm: Observation versus RT followed by PCV >40, subtotal resection, astro/mixed, big tumor: Treat with RT + chemo PCV vs TMZ Mixed prognostic factors: Individualized therapy; avoiding toxicity should be prioritized Recurrence/Progression Confirm diagnosis
LGG: Future Considerations IDH1 inhibitors are entering into clinical trials Is there a potential role in the treatment of LGG? IDH1 wild type LGG behave similar to malignant glioma (e.g. glioblastoma) unpublished data from TCGA Should we consider IDH1 mutant tumors a different disease? Chemotherapy-induced tumor changes 25
LGG: Future Considerations: Chemotherapy-induced tumor mutations Could early TMZ alter the disease biology and progression trajectory? C>T/G>A transitions at CpC and CpT dinucleotides, a signature of TMZ induced mutagenesis Johnson et al, Science 2014 26
Conclusions No current consensus on management of newly diagnosed LGG Most agree on maximal safe debulking Post-op treatment decisions often based on extent of resection and age If treatment warranted, some advocate chemotherapy if 1p/19q co-deleted RTOG 98-02 has provided important information Prognostic differences between low grade oligodendroglioma and astrocytic tumors Marked differences in rate of recurrence after surgery Confirmed impact of prognostic factors: age, KPS, extent of resection (in addition to histology) with 1p/19q data pending Chemotherapy has a role in recurrent disease and may benefit in newly diagnosed Temozolomide may have a better toxicity it profile compared with PCV TMZ and other chemotherapy could alter disease biology (hypermutation) Impact of IDH1 uncertain, although prognostic significance is supported
Thank you for your attention. jdegroot@mdanderson.org
Role of Radiation in LGG 3 large cooperative group randomized trials EORTC 22845: Observation (radiation at progression) vs. 54 Gy 5 year survival: 66 vs 63% EORTC 22844: 45 vs 59.4 Gy 5 year survival: 58 vs. 59% NCCTG: 50.4 vs. 64.8 Gy 5 year survival 72 vs 64%
LGG: Radiation Conclusions Early vs late radiation does not improve overall survival (does prolong PFS) What does this mean for QOL and neurocognitive function? Optimal dose is uncertain; no apparent gain from higher doses Most subsequent studies have used an intermediate Most subsequent studies have used an intermediate dose (54-57 Gy)